CXCR7 antagonists

ABSTRACT

Compounds having formula I,or pharmaceutically acceptable salts, hydrates or N-oxides thereof are provided and are useful for binding to CXCR7, and treating diseases that are dependent, at least in part, on CXCR7 activity. Accordingly, the present invention provides in further aspects, compositions containing one or more of the above-noted compounds in admixture with a pharmaceutically acceptable excipient.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/379,599 filed Apr. 9, 2019, which is a continuation of U.S.application Ser. No. 15/692,739 filed Aug. 31, 2017 (now U.S. Pat. No.10,287,292), which is a continuation of U.S. patent application Ser. No.14/836,172 filed Aug. 26, 2015 (now U.S. Pat. No. 9,783,544), which is acontinuation of U.S. patent application Ser. No. 14/091,641 filed Nov.27, 2013 (now U.S. Pat. No. 9,169,261), which application claims thebenefit of priority to U.S. Provisional Application No. 61/731,463 filedNov. 29, 2012, each of which is incorporated herein by reference in itsentirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

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BACKGROUND OF THE INVENTION

The present invention is directed to novel compounds and pharmaceuticalcompositions that inhibit the binding of the SDF-1 chemokine (also knownas the CXCL12 chemokine) or I-TAC (also known as CXCL11) to thechemokine receptor CXCR7. These compounds are useful in preventing tumorcell proliferation, tumor formation, tumor vascularization, metastasis,inflammatory diseases including, but not limited to arthritis, renalinflammatory disorders and multiple sclerosis, conditions of impropervasculatization including, but not limited to wound healing, treatmentof HIV infectivity, and treatment of stem cell differentiation andmobilization disorders (see also, co-pending U.S. Ser. Nos. 10/912,638,11/407,729 and 11/050,345).

Chemokines are a superfamily of small, cytokine-like proteins thatinduce cytoskeletal rearrangement, firm adhesion to endothelial cells,and directional migration and may also effect cell activation andproliferation. Chemokines act in a coordinated fashion with cell surfaceproteins to direct the specific homing of various subsets of cells tospecific anatomical sites.

Early research efforts by a number of groups have indicated a role forthe chemokine receptor CXCR4 in metastasis and tumor growth. Muller, etal., “Involvement of Chemokine Receptors in Breast Cancer Metastasis,”Nature, 410:50-56 (2001) demonstrated that breast tumor cells usechemokine-mediated mechanisms, such as those regulating leukocytetrafficking, during the process of metastasis. Tumor cells express adistinct, non-random pattern of functionally active chemokine receptors.Signaling through CXCR4 mediates actin polymerization and pseudopodiaformation in breast cancer cells, and induces chemotactic and invasiveresponses. Additionally, the organs representing the main sites ofbreast cancer metastasis (such as lymph nodes, bone marrow, and lungs)are the most abundant sources of ligand for the CXCR4 receptor.

Using immunodeficient mice, Muller and colleagues succeeded in reducingthe metastasis of injected human breast cancer cells by treating micewith an antibody known to bind CXCR4. Their finding suggests that breastcancer metastasis could be reduced by treating a patient with a CXCR4antagonist.

Bertolini, et al., “CXCR4 Neutralization, a Novel Therapeutic Approachfor Non-Hodgkin's Lymphoma,” Cancer Research, 62:3106-3112 (2002)demonstrated a reduction of tumor volume as well as prolonged survivalof immunodeficient mice injected with human lymphoma cells treated withanti-CXCR4 antibodies. They interpreted their finding to mean that tumorvolume could be reduced by treating a patient with a CXCR4 antagonist.

More recent studies suggest that another chemokine receptor, CXCR7, mayalso be a target in the treatment of cancer. CXCR7 is preferentiallyexpressed in transformed cells over normal cells, with detectableexpression in a number of human cancers. In vitro studies indicate thatproliferation of CXCR7 expressing cells can be inhibited by anantagonist of CXCR7. In vivo studies in mice indicate that CXCR7antagonists can inhibit tumor formation and tumor growth.

The potential importance of CXCR7 is illustrated by an alternativeinterpretation of the reduction in tumor volume seen by Bertolini andcolleagues. This reduction could clearly be the result of anantibody-mediated clearance, and not the result of the anti-CXCR4antibody as originally believed. In an antibody-mediated clearance, anyantibody that recognized a protein on the cell surface of the lymphomacells would have had the same effect as that attributed to theanti-CXCR4 antibody. Unfortunately, Bertolini and colleagues studies areinconclusive as to whether the observed tumor response was due toantibody-mediated clearance or interaction with CXCR4.

However it is now known that the lymphoma cells used by Bertolini andcolleagues express both CXCR4 and CXCR7. SDF-1 is the only ligand forCXCR4. SDF-1 and I-TAC both bind CXCR7. Using anti-SDF-1 antibody, ithas now been shown that antagonists of CXCR7 are responsible for thereduction in tumor load and increased survival rate. Because SDF-1 isthe only ligand for CXCR4, one would expect neutralization of SDF-1 withanti-SDF-1 antibody would be equivalent to the neutralization of CXCR4with anti-CXCR4 antibody. However, experiments using an anti-SDF-1antibody demonstrated only a partial reduction in tumor load and anincreased survival rate. As a result, CXCR7 is the likely target, as thecontinued activity appears due to the interactions of the second ligand,I-TAC, with CXCR7.

Until recently, the possible importance of CXCR7 in tumor cellproliferation, tumor growth, and metastasis was unknown. Now, evidencepoints to the ability of certain CXCR7 antagonists to prevent the growthand spread of cancer, and expression patterns indicate a limited tissuedistribution for the CXCR7 receptor which correlates to tumorigenesis.

Moreover, it has been discovered that CXCR7 can serve as a co-receptorfor certain genetically divergent human immunodeficiency virus (HIV) andsimian immunodeficiency virus (SIV), in particular for the HIV-2-ROD, anX4-tropic isolate (Shimizu, N. et al., J. Virol., (2000) 74: 619-626;Balabanian, K., et al., J. Biol. Chem., in press; published on Aug. 17,2005 as Manuscript M508234200).

Still further, SDF-1, has been described to have a role in themobilization of hematopoietic progenitor cells and stem cells, and inparticular of those cells bearing the CXCR4 receptor, from specifichematopoietic tissues including bone marrow has been described (Hattori,K., et al., Blood, (2000) 97:3354-3360; WO 2005/000333, the disclosureof which are incorporated herein by reference). More recent studiessuggest that the CXCR7 receptor may also play a part in stem cellmobilization processes.

In view of the above, it is apparent that compounds that are able tobind specifically to CXCR7 receptors can be useful for treating diseasesand other biological conditions that may benefit from such interactions.The present invention provides such compounds along with pharmaceuticalcompositions and related methods for treatment.

BRIEF SUMMARY OF THE INVENTION

The present invention provides, in one aspect, compounds having formulaI,

or pharmaceutically acceptable salts, hydrates or N-oxides thereof. Thevarious groups (e.g., R¹, R², R³, R⁴, Z, X^(a), X^(b), X^(c) and thesubscript n) are described in the Detailed Description of the Invention.

The compounds provided herein are useful for binding to CXCR7, andtreating diseases that are dependent, at least in part, on CXCR7activity. Accordingly, the present invention provides in furtheraspects, compositions containing one or more of the above-notedcompounds in admixture with a pharmaceutically acceptable excipient.

In still another aspect, the present invention provides methods fortreating various diseases, discussed further herein, comprisingadministering to a subject in need to such treatment a therapeuticallyeffective amount of a compound of the above formula for a period of timesufficient to treat the disease.

In yet another aspect, the present invention provides methods ofdiagnosing disease in an individual. In these methods, the compoundsprovided herein are administered in labeled form to a subject, followedby diagnostic imaging to determine the presence or absence of CXCR7. Ina related aspect, a method of diagnosing disease is carried out bycontacting a tissue or blood sample with a labeled compound as providedherein and determining the presence, absence, or amount of CXCR7 in thesample.

In some embodiments, an amount of a chemotherapeutic agent or radiationis administered to the subject prior to, subsequent to or in combinationwith the compounds of the present invention. In some embodiments, theamount is sub-therapeutic when the chemotherapeutic agent or radiationis administered alone.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable

DETAILED DESCRIPTION OF THE INVENTION I. Abbreviation and Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of such unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “cycloalkyl”refers to hydrocarbon rings having the indicated number of ring atoms(e.g., C₃₋₆cycloalkyl) and being fully saturated or having no more thanone double bond between ring vertices. “Cycloalkyl” is also meant torefer to bicyclic and polycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term“cycloalkenyl” refers to a cycloalkyl group having at least one doublebond between ring vertices. Examples of cycloalkenyl are cyclopentenyland cyclohexenyl. The term “spirocycloalkyl” refers to a cycloalkylgroup in which a single ring vertex is attached to two othernon-hydrogen portions of the molecule. A spirocycloalkyl substituent isone in which two carbon atoms of an alkylene chain (typically thetermini of the alkylene chain) are attached to the same carbon atom inthe remainder of the molecule. The term “heterocycloalkyl” refers to acycloalkyl group that contain from one to five heteroatoms selected fromN, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Theheterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ringsystem. Non limiting examples of heterocycloalkyl groups includepyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine,and the like. A heterocycloalkyl group can be attached to the remainderof the molecule through a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms. Similarly, “alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively.

As used herein, a wavy line, “

”, that intersects a single, double or triple bond in any chemicalstructure depicted herein, represent the point attachment of the single,double, or triple bond to the remainder of the molecule.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl groups include phenyl, naphthyl and biphenyl, whilenon-limiting examples of heteroaryl groups include pyridyl, pyridazinyl,pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl,isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl,thiazolyl, furyl, thienyl and the like. Substituents for each of theabove noted aryl and heteroaryl ring systems are selected from the groupof acceptable substituents described below.

The term “arylalkyl” is meant to include those radicals in which an arylgroup is attached to an alkyl group (e.g., benzyl, phenethyl, and thelike). Similarly, the term “heteroaryl-alkyl” is meant to include thoseradicals in which a heteroaryl group is attached to an alkyl group(e.g., pyridylmethyl, thiazolylethyl, and the like).

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be avariety of groups selected from: -halogen, —OR′, —NR′R″, —SR′,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstitutedaryl, aryl substituted with 1-3 halogens, unsubstituted C₁₋₈ alkyl, C₁₋₈alkoxy or C₁₋₈ thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring. For example, —NR′R″ is meant to include 1-pyrrolidinyland 4-morpholinyl.

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, unsubstituted aryl and heteroaryl, (unsubstitutedaryl)-C₁₋₄ alkyl, and unsubstituted aryloxy-C₁₋₄ alkyl. Other suitablesubstituents include each of the above aryl substituents attached to aring atom by an alkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)-U-, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “progenitor cells” and “stem cells” are usedinterchangeably. “Progenitor cells” and “stem cells” refer to cellsthat, in response to certain stimuli, can form differentiated celllineages, including but not limited to hematopoietic, mesenchymal,epithelial, neuronal, renal or myeloid cells. The presence ofprogenitor/stem cells can be assessed by the ability of the cells in asample to form colony-forming units of various types, including, forexample, CFU-GM (colony-forming units, granulocyte-macrophage); CFU-GEMM(colony-forming units, multipotential); BFU-E (burst-forming units,erythroid); HPP-CFC (high proliferative potential colony-forming cells);or other types of differentiated colonies which can be obtained inculture using known protocols.

Hematopoetic progenitor/stem cells are often positive for CD34. Somestem cells do not contain this marker, however. These CD34+ cells can beassayed using fluorescence activated cell sorting (FACS) and thus theirpresence can be assessed in a sample using this technique.Alternatively, such cells can be assayed by FACS for the presence ofc-kit receptor (CD117), absence of lineage specific markers (e.g., CD2,CD3, CD4, CD5, CD8, NK1.1, B220, TER-119, and Gr-1 in mice and CD3,CD14, CD16, CD19, CD20 and CD56 in humans).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occuring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. In some embodiments, the compounds of the inventionare present in an enantiomerically enriched form, wherein the amount ofenantiomeric excess for a particular enantiomer is calculated by knownmethods. The preparation of enantiomerically enriched forms is also wellknown in the art and can be accomplished using, for example, chiralresolution via chromatography or via chiral salt formation.Additionally, different conformers are contemplated by the presentinvention, as well as distinct rotamers. Conformers are conformationalisomers that can differ by rotations about one or more a bonds. Rotamersare conformers that differ by rotation about only a single a bond. Stillfurther, the compounds of the present invention may also containunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. Accordingly, in some embodiments, thecompounds of the invention are present in isotopically enriched form.Unnatural proportions of an isotope may be defined as ranging from theamount found in nature to an amount consisting of 100% of the atom inquestion. For example, the compounds may incorporate radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) orcarbon-13 (¹³C). Such isotopic variations can provide additionalutilities to those described elsewhere with this application. Forinstance, isotopic variants of the compounds of the invention may findadditional utility, including but not limited to, as diagnostic and/orimaging reagents, or as cytotoxic/radiotoxic therapeutic agents.Additionally, isotopic variants of the compounds of the invention canhave altered pharmacokinetic and pharmacodynamic characteristics whichcan contribute to enhanced safety, tolerability or efficacy duringtreatment. All isotopic variations of the compounds of the presentinvention, whether radioactive or not, are intended to be encompassedwithin the scope of the present invention.

“CXCR7” also referred to as “RDC1” or “CCXCKR2” refers to aseven-transmembrane domain presumed G-protein coupled receptor (GPCR).The CXCR7 dog ortholog was originally identified in 1991. See, Libert etal. Science 244:569-572 (1989). The dog sequence is described in Libertet al., Nuc. Acids Res. 18(7):1917 (1990). The mouse sequence isdescribed in, e.g., Heesen et al., Immunogenetics 47:364-370 (1998). Thehuman sequence is described in, e.g., Sreedharan et al., Proc. Natl.Acad. Sci. USA 88:4986-4990 (1991), which mistakenly described theprotein as a receptor of vasoactive intestinal peptide. “CXCR7” includessequences that are substantially similar to or conservatively modifiedvariants of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ IDNO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10.

II. General

Compounds of the present invention can inhibit the binding of ligands tothe CXCR7 receptor and are useful in the treatment of various diseases,including cancer, particularly solid tumor cancers and lymphomas. Morerecently, the inhibition of ligand binding to CXCR7 was noted to reducethe severity of rheumatoid arthritis in an animal model.

Those of skill in the art will understand that agents that modulateCCX-CKR2 activity (CXCR7 activity) can be combined in treatment regimenswith other anti-angiogenesis agents and/or with chemotherapeutic agentsor radiation and/or other anti-arthritis agents. In some cases, theamount of chemotherapeutic agent or radiation is an amount which wouldbe sub-therapeutic if provided without combination with ananti-angiogenic agent. Those of skill in the art will appreciate that“combinations” can involve combinations in treatments (i.e., two or moredrugs can be administered as a mixture, or at least concurrently or atleast introduced into a subject at different times but such that bothare in the bloodstream of a subject at the same time). Additionally,compositions of the current invention may be administered prior to orsubsequent to a second therapeutic regimen, for instance prior to orsubsequent to a dose of chemotherapy or irradiaition.

III. Embodiments of the Invention

A. Compounds

The present invention provides, in one aspect, compounds having formulaI,

or pharmaceutically acceptable salts, hydrates, N-oxides, isotopicallyenriched or enantiomerically enriched versions and rotamers thereof. Informula I, each of ring vertices X^(a), X^(b) and X^(c) is independentlyselected from N, NH, N(R²), O, CH and C(R²). Additionally, the subscriptn is 0, 1 or 2. The letter Z represents a group selected from:

-   -   (i) monocyclic or fused-bicyclic aryl and heteroaryl, wherein        the heteroaryl group has from 1-4 heteroatoms as ring members        selected from N, O and S; and wherein said aryl and heteroaryl        groups are optionally substituted with from 1 to 5 R⁵        substituents;    -   (ii) monocyclic four-, five-, six- or seven-membered ring        selected from the group consisting of cycloalkane, and        heterocycloalkane, wherein the heterocycloalkane rings have from        1-3 heteroatoms as ring members selected from N, O and S; and        wherein each of said monocyclic Z rings are optionally        substituted with from 1 to 3 R⁵ substituents.

R¹ is a member selected from H and C₁₋₈ alkyl, wherein the alkyl portionis optionally substituted with halogen, —NR^(a)R^(b), —OR^(a),—CO₂R^(a), and —CONR^(a)R^(b).

Each R² is independently selected from H, halogen, CN, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ hydroxyalkyl, —OR^(a), —CO₂R^(a), —X—CO₂R^(a),—NR^(a)R^(b), —CONR^(a)R^(b) and —X—CONR^(a)R^(b).

R³ is selected from H, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl,—CO₂R^(a), —X—CO₂R^(a), —CONR^(a)R^(b) and —X—CONR^(a)R^(b).

Each R⁴, when present, is independently selected from C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ hydroxyalkyl, —OR^(a), —CO₂R^(a), —X—CO₂R^(a),—NR^(a)R^(b), —CONR^(a)R^(b) and —X—CONR^(a)R^(b).

Each R⁵ is independently selected from halogen, CN, —X—CN, C₁₋₈ alkyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₅ spirocycloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, —OR^(a), —CO₂R^(a),—X—CO₂R^(a), —NR^(a)R^(b), —CONR^(a)R^(b), —X—CONR^(a)R^(b), aryl, 5- or6-membered heteroaryl, and 3-, 4-, 5- or 6-membered heterocyclic whereinthe heteroatoms present as ring vertices of the heteroaryl andheterocyclic rings are selected from N, O and S, and wherein the aryl,heteroaryl and hetereocyclic portions of R⁵ are optionally furthersubstituted with 1-3 R^(a).

Each R^(a) and R^(b) is independently selected from hydrogen, hydroxyl,halogen, cyano, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkylalkyl, amino, C₁₋₈ alkylamino, di C₁₋₈alkylamino, carboxamide, carboxy C₁₋₄ alkyl ester, carboxylic acid, and—SO₂—C₁₋₈ alkyl.

Each X is a C₁₋₄ alkylene linking group or a linking group having theformula —(CH₂)_(m)O(CH₂)_(p)—, wherein the subscripts m and p areinteger of from 0 to 5, and m+p is from 0 to 6, wherein any of themethylene portions of X are optionally substituted with one or twomethyl groups. In one group of embodiments, each X is independentlyselected from —OCH₂—, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —OC(CH₃)₂—,—OCH₂C(CH₃)₂—, —OCH₂CH₂C(CH₃)₂—, —CH₂—, —C(CH₃)₂— and —CH₂CH₂—. Inanother group of embodiments, each X is selected from —O—, —CH₂—,—OCH₂—, —OCH₂CH₂—, —C(CH₃)₂— and —CH₂CH₂—.

A number of embodiments are provided in the present invention.

(A) In one group of embodiments, Z is monocyclic or fused-bicyclicheteroaryl, having 1-3 heteroatoms as ring members selected from N, Oand S; and wherein said heteroaryl group is optionally substituted withfrom 1 to 5 R⁵ substituents.

(B) In another group of embodiments, Z is monocyclic or fused-bicyclicheteroaryl selected from the group consisting of imidazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, thiazole, oxazole,oxadiazole, pyrimidine, pyrazine, pyridazine, and quinazoline, each ofwhich is optionally substituted with from 1-2 R⁵ substituents.

(C) In still another group of embodiments, Z is is a 5-memberedheteroaryl group substituted with one R⁵ group selected from anoptionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkylring, and optionally with up to two additional R⁵ groups which areselected from halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and CH₂CN.

(D) In other embodiments, Z is selected from:

wherein R⁵ has the meaning provided with reference to formula I above.

(E) In yet another group of embodiments, the compounds of formula I arethose in

-   -   which Z is

wherein each Q is independently selected from the group consisting of N,CH, and C(R⁵), and R⁵ has the meaning provided with reference to formulaI above.

Within any of the embodiments provided in (A) through (E) or withreference to formula I, are other selected embodiments.

(1) In one group of embodiments, n is zero.

(2) In another group of embodiments, R¹ is H.

In another group of embodiments, the compounds of formula I arerepresented by:

Selected embodiments of formula Ia, include each of the embodiments forZ, identified in (A) through (E) above,

In one specific group of embodiments of formula I or Ia,

(F) The bicyclic portion having X^(a), X^(b) and X^(c) as ring verticesis selected from:

In another specific group of embodiments of formula Ia,

-   -   (G) The bicyclic portion having X^(a), X^(b) and X^(c) as ring        vertices is selected from:

In still another specific group of embodiments of formula Ia,

(H) The bicyclic portion having X^(a), X^(b) and X^(c) as ring verticesis selected from:

In one specific group of embodiments of formula Ia,

(I) The bicyclic portion having X^(a), X^(b) and X^(c) as ring verticesis selected from:

In another specific group of embodiments of formula Ia,

(J) The bicyclic portion having X^(a), X^(b) and X^(c) as ring verticesis selected from:

In certain selected embodiments, the compounds of formula Ia, and theembodiments identified as (F), (G), (H), (I), and (J) are compounds inwhich Z is selected from the embodiments identified as (A) through (E),above, particularly those wherein Z is a 5-membered heteroaryl groupsubstituted with one R⁵ group selected from an optionally substitutedaryl, heteroaryl, cycloalkyl, or a heterocycloalkyl ring, and optionallywith up to two additional R⁵ groups which are selected from halogen,C₁₋₄ alkyl, C₁₋₄ haloalkyl, and CH₂CN.

In yet another specific group of embodiments, for formula I or Ia, andembodiments identified as (F), (G), (H), (I), and (J), Z is selectedfrom the group consisting of:

wherein R⁵ has the meaning provided with reference to formula I above.

In still another specific group of embodiments, with reference toformula I or Ia, and embodiments identified as (F), (G), (H), (I), and(J), Z has the formula:

wherein each Q is independently selected from the group consisting of N,CH, and C(R⁵).

In one specific group of embodiments, the compounds have the formula:

wherein R^(a) and each R² have the meanings provided with reference toformula I.

Within any of the embodiments provided in (A) through (J), as well asthe embodiments which are combinations (for example (A) and (F); (B) and(G); (A) and (H), and the like), are still other selected embodiments:

(a) wherein the subscript n is 0;

(b) wherein n is 0, and R¹ is H or methyl;

(c) wherein n is 0, and R¹ is H or methyl and R² is H or C₁₋₈ alkyl andR³ is hydrogen;

(d) wherein n is 0, and each of R² and R³ is hydrogen;

(e) wherein n is 0, each R² is hydrogen and R³ is selected from thegroup consisting of methyl, ethyl, —CONH₂, and —CH₂OH;

(f) wherein each R² is hydrogen.

One of skill in the art will appreciate that specific embodiments of theinvention are compounds of formula I or Ia, wherein features of thecompound are further defined by the combinations of embodiments,including (A)+(F); (A)+(G); (A)+(H); (A)+(I); and (A)+(J); each ofwhich, in further selected embodiments is independently combined witheach of selected embodiments (a) through (f). Similarly, selectedcompounds of formula I or Ia, are those wherein features of the compoundare further defined by the combinations of embodiments, including(B)+(F); (B)+(G); (B)+(H); (B)+(I); and (B)+(J); each of which, infurther selected embodiments is independently combined with each ofselected embodiments (a) through (f). Still other selected compounds offormula I or Ia, are those wherein features of the compound are furtherdefined by the combinations of embodiments, including (C)+(F); (C)+(G);(C)+(H); (C)+(I); and (C)+(J); each of which, in further selectedembodiments is independently combined with each of selected embodiments(a) through (f). Other selected compounds of formula I or Ia, are thosewherein features of the compound are further defined by the combinationsof embodiments, including (D)+(F); (D)+(G); (D)+(H); (D)+(I); and(D)+(J); each of which, in further selected embodiments is independentlycombined with each of selected embodiments (a) through (f). Still otherselected compounds of formula I or Ia, are those wherein features of thecompound are further defined by the combinations of embodiments,including (E)+(F); (E)+(G); (E)+(H); (E)+(I); and (E)+(J); each ofwhich, in further selected embodiments is independently combined witheach of selected embodiments (a) through (f).

In one selected group of embodiments, the compound is selected fromthose provided in the Examples below, or in Table 1.

In each of the selected embodiments, the noted compounds may be presentin a pharmaceutically acceptable salt or hydrate form.

Still further, for those compounds shown above without stereochemistry,the present invention is also directed to chiral forms of each of thecompounds, as well as enantiomerically enriched forms of the notedcompounds. Enantiomerically enriched forms can be prepared using chiralchromatography according to well known methods practiced in the art or,for example, by chiral resolution with a chiral salt form. In someembodiments, the enantiomeric excess for an enantiomerically enrichedform is at least 10%, 20%, 30%, 40%, 50%, 60% or more. In still otherembodiments, an enantiomerically enriched form is provided that is atleast 70%, 80%, 90%, 95%, or more.

Preparation of Compounds

Certain compounds of the invention can be prepared following methodologyas described in the Examples section of this document. In addition thesyntheses of certain intermediate compounds that are useful in thepreparation of compounds of the invention are also described.

B. Compositions

In addition to the compounds provided above, compositions for modulatingCXCR7 activity in humans and animals will typically contain apharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present invention are employed. As used herein, topicalapplication is also meant to include the use of mouth washes andgargles.

The compounds of this invention may also be coupled a carrier that is asuitable polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like.

C. Methods of Use

While not wishing to be bound by any particular theory, the compoundsand compositions of the present invention are considered to provide atherapeutic effect by inhibiting the binding of SDF-1 and/or I-TAC tothe CXCR7 receptor. Therefore, the compounds and compositions of thepresent invention can be used in the treatment or prevention of diseasesor disorders in a mammal in which the inhibition of binding of SDF-1and/or I-TAC to the CXCR7 receptor would provide a therapeutic effect.

In one embodiment, a preferred method of inhibiting the binding of thechemokines SDF-1 and/or I-TAC to a CXCR7 receptor includes contactingone or more of the previously mentioned compounds with a cell thatexpresses the CXCR7 receptor for a time sufficient to inhibit thebinding of these chemokines to the CXCR7 receptor.

In some embodiments, the compounds and compositions of the invention areadministered to a subject having cancer. In some cases, CXCR7 modulatorsare administered to treat cancer, e.g., carcinomas, gliomas,mesotheliomas, melanomas, lymphomas, leukemias (including acutelymphocytic leukemias), adenocarcinomas, breast cancer, ovarian cancer,cervical cancer, glioblastoma, leukemia, lymphoma, prostate cancer, andBurkitt's lymphoma, head and neck cancer, colon cancer, colorectalcancer, non-small cell lung cancer, small cell lung cancer, cancer ofthe esophagus, stomach cancer, pancreatic cancer, hepatobiliary cancer,cancer of the gallbladder, cancer of the small intestine, rectal cancer,kidney cancer, renal cancer, bladder cancer, prostate cancer, penilecancer, urethral cancer, testicular cancer, cervical cancer, vaginalcancer, uterine cancer, ovarian cancer, thyroid cancer, parathyroidcancer, adrenal cancer, pancreatic endocrine cancer, carcinoid cancer,bone cancer, skin cancer, retinoblastomas, Hodgkin's lymphoma,non-Hodgkin's lymphoma (see, CANCER: PRINCIPLES AND PRACTICE (DeVita, V.T. et al. eds 1997) for additional cancers); as well as brain andneuronal dysfunction, such as Alzheimer's disease, multiple sclerosisand demyelinating diseases; hypertensive disorders such as pulmonaryarterial hypertension; kidney dysfunction; renal dysfunction; rheumatoidarthritis; allograft rejection; atherosclerosis (and elevatedcholesterol levels); asthma; glomerulonephritis; contact dermatitis;inflammatory bowel disease; colitis; psoriasis; reperfusion injury; aswell as other disorders and diseases described herein. In someembodiments, the subject does not have Kaposi's sarcoma, multicentricCastleman's disease or AIDS-associated primary effusion lymphoma.

The present invention also encompasses decreasing angiogenesis in anysubject in need thereof by administering the compounds and compositionsof the invention. For example, decreasing CXCR7 activity by contactingCXCR7 with a compound of the invention, thereby decreasing angiogenesis,is useful to inhibit formation, growth and/or metastasis of tumors,especially solid tumors. Description of embodiments relating tomodulated CXCR7 and angiogenesis are described in, e.g., U.S. patentapplication Ser. No. 11/050,345.

Other disorders involving unwanted or problematic angiogenesis includerheumatoid arthritis; psoriasis; ocular angiogenic diseases, forexample, diabetic retinopathy, retinopathy of prematurity, maculardegeneration, corneal graft rejection, neovascular glaucoma, retrolentalfibroplasia, rubeosis; Osler-Webber Syndrome; myocardial angiogenesis;plaque neovascularization; telangiectasia; hemophiliac joints;angiofibroma; disease of excessive or abnormal stimulation ofendothelial cells, including intestinal adhesions, Crohn's disease, skindiseases such as psoriasis, excema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, atherosclerosis, scleroderma, wound granulation andhypertrophic scars, i.e., keloids, and diseases that have angiogenesisas a pathologic consequence such as cat scratch disease and ulcers(Helicobacter pylori), can also be treated with antibodies of theinvention. Angiogenic inhibitors can be used to prevent or inhibitadhesions, especially intra-peritoneal or pelvic adhesions such as thoseresulting after open or laproscopic surgery, and burn contractions.Other conditions which should be beneficially treated using theangiogenesis inhibitors include prevention of scarring followingtransplantation, cirrhosis of the liver, pulmonary fibrosis followingacute respiratory distress syndrome or other pulmonary fibrosis of thenewborn, implantation of temporary prosthetics, and adhesions aftersurgery between the brain and the dura. Endometriosis, polyposis,cardiac hypertrophyy, as well as obesity, may also be treated byinhibition of angiogenesis. These disorders may involve increases insize or growth of other types of normal tissue, such as uterinefibroids, prostatic hypertrophy, and amyloidosis. Compounds andcompositions of the present invention may be used prophylactically ortherapeutically for any of the disorders or diseases described herein.

Decreasing CXCR7 activity with the compounds and compositions of thepresent invention can also be used in the prevention ofneovascularization to effectively treat a host of disorders. Thus, forexample, the decreasing angiogenesis can be used as part of a treatmentfor disorders of blood vessels (e.g., hemangiomas and capillaryproliferation within atherosclerotic plaques), muscle diseases (e.g.,myocardial angiogenesis, myocardial infarction or angiogenesis withinsmooth muscles), joints (e.g., arthritis, hemophiliac joints, etc.), andother disorders associated with angiogenesis. Promotion of angiogenesiscan also aid in accelerating various physiological processes andtreatment of diseases requiring increased vascularization such as thehealing of wounds, fractures, and burns, inflammatory diseases, ischericheart, and peripheral vascular diseases. The compounds of the presentinvention can also provide benefit in conditions in which normal bloodflow is restricted, such as pulmonary hypertension.

The compounds and compositions of the present invention may also be usedto enhance wound healing. Without intending to limit the invention to aparticular mechanism of action, it may be that antagonism of CXCR7allows for endogenous ligands to instead bind to lower affinityreceptors, thereby triggering enhanced wound healing. For example, SDF-1binds to both CXCR7 and CXCR4, but binds to CXCR4 with a lower affinity.Similarly, I-TAC binds to CXCR3 with a lower affinity than I-TAC bindsto CXCR7. By preventing binding of these ligands to CXCR7, CXCR7antagonists may allow the ligands to bind to the other receptors,thereby enhancing wound healing. Thus, the antagonism of CXCR7 toenhance wound healing may be mediated by a different mechanism thanenhancing wound healing by stimulating CXCR7 activity with an agonist.

Aside from treating disorders and symptoms associated withneovascularization, the inhibition of angiogenesis can be used tomodulate or prevent the occurrence of normal physiological conditionsassociated with neovascularization. Thus, for example the compounds andcompositions can be used as a birth control. In accordance with thepresent invention, decreasing CXCR7 activity within the ovaries orendometrium can attenuate neovascularization associated with ovulation,implantation of an embryo, placenta formation, etc.

Inhibitors of angiogenesis have yet other therapeutic uses. For example,the compounds and compositions of the present invention may be used forthe following:

-   -   (a) Adipose tissue ablation and treatment of obesity. See, e.g,        Kolonin et al., Nature Medicine 10(6):625-632 (2004);    -   (b) Treatment of preclampsia. See, e.g., Levine et al., N. Engl.        J Med. 350(7): 672-683 (2004); Maynard, et al., J Clin. Invest.        111(5): 649-658 (2003); and    -   (c) Treatment of cardiovascular disease. See, e.g., March, et        al., Am. J Physiol. Heart Circ. Physiol. 287:H458-H463 (2004);        Rehman et al., Circulation 109: 1292-1298 (2004).

Methods of Treating Cancer

More specifically, the present invention also provides a method oftreating cancer. A preferred method of treating cancer, includesadministering a therapeutically effective amount of one or more of thepreviously mentioned compounds (or salts thereof) to a cancer patientfor a time sufficient to treat the cancer.

For treatment, the compositions of the present invention may beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, ICV, intracisternal injection or infusion, subcutaneousinjection, or implant), by inhalation spray, nasal, vaginal, rectal,sublingual, or topical routes of administration and may be formulated,alone or together, in suitable dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles appropriate for each route of administration.

In some embodiments, CXCR7 modulators of the present invention can beadministered in combination with other appropriate therapeutic agents,including, e.g., chemotherapeutic agents, radiation, etc. It isunderstood that such administration may be prior to, subsequent to or inunison with the second therapeutic agent, such that the therapeuticeffects of the second agent are enhanced when compared to administrationof the second agent in the absence of the CXCR7 modulator. Selection ofthe appropriate agents for use in combination therapy may be made by oneof ordinary skill in the art, according to conventional pharmaceuticalprinciples. The combination of therapeutic agents may actsynergistically to effect the treatment or prevention of the variousdisorders such as, e.g., cancer, wounds, kidney dysfunction, braindysfunction or neuronal dysfunction. Using this approach, one may beable to achieve therapeutic efficacy with lower dosages of each agent,thus reducing the potential for adverse side effects.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

Standard in vivo assays demonstrating that the compositions of thepresent invention are useful for treating cancer include those describedin Bertolini, F., et al., Endostatin, an antiangiogenic drug, inducestumor stabilization after chemotherapy or anti-CD20 therapy in aNOD/SCID mouse model of human high-grade non-Hodgkin lymphoma. Blood,No. 1, Vol. 96, pp. 282-87 (1 Jul. 2000); Pengnian, L., Antiangiogenicgene therapy targeting the endothelium-specific receptor tyrosine kinaseTie2. Proc. Natl. Acad. Sci. USA, Vol. 95, pp. 8829-34 (July 1998); andPulaski, B. Cooperativity of Staphylococcal aureus Enterotoxin BSuperantigen, Major Histocompatibility Complex Class II, and CD80 forImmunotherapy of Advanced Spontaneous Metastases in a ClinicallyRelevant Postoperative Mouse Breast Cancer Model. Cancer Research, Vol.60, pp. 2710-15 (May 15, 2000).

In the treatment or prevention of conditions which require chemokinereceptor modulation an appropriate dosage level will generally be about0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0,10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0,400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, hereditary characteristics, generalhealth, sex and diet of the subject, as well as the mode and time ofadministration, rate of excretion, drug combination, and the severity ofthe particular condition for the subject undergoing therapy.

The compounds and compositions of the present invention can be combinedwith other compounds and compositions having related utilities toprevent and treat cancer and diseases or conditions associated withCXCR7 signaling. Such other drugs may be administered, by a route and inan amount commonly used therefor, contemporaneously or sequentially witha compound or composition of the present invention. When a compound orcomposition of the present invention is used contemporaneously with oneor more other drugs, a pharmaceutical composition containing such otherdrugs in addition to the compound or composition of the presentinvention is preferred. Accordingly, the pharmaceutical compositions ofthe present invention include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to a compound orcomposition of the present invention. Examples of other therapeuticagents that may be combined with a compound or composition of thepresent invention, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: cisplatin,paclitaxel, methotrexate, cyclophosphamide, ifosfamide, chlorambucil,carmustine, carboplatin, vincristine, vinblastine, thiotepa, lomustine,semustine, 5-fluorouracil and cytarabine. The weight ratio of thecompound of the present invention to the second active ingredient may bevaried and will depend upon the effective dose of each ingredient.Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with a secondanticancer agent, the weight ratio of the compound of the presentinvention to the second agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

Methods of Treating Inflammation

Still further, the compounds and compositions of the present inventionare useful for the treatment of inflammation, and can be combined withother compounds and compositions having therapeutic utilities that mayrequire treatment either before, after or simultaneously with thetreatment of cancer or inflammation with the present compounds.Accordingly, combination methods and compositions are also a componentof the present invention to prevent and treat the condition or diseaseof interest, such as inflammatory or autoimmune disorders, conditionsand diseases, including inflammatory bowel disease, rheumatoidarthritis, osteoarthritis, psoriatic arthritis, polyarticular arthritis,multiple sclerosis, allergic diseases, psoriasis, atopic dermatitis andasthma, and those pathologies noted above.

For example, in the treatment or prevention of inflammation orautoimmunity or for example arthritis associated bone loss, the presentcompounds and compositions may be used in conjunction with ananti-inflammatory or analgesic agent such as an opiate agonist, alipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, acyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, aninterleukin inhibitor, such as an interleukin-1 inhibitor, an NMDAantagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non steroidal anti-inflammatory agent, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.Similarly, the instant compounds and compositions may be administeredwith an analgesic listed above; a potentiator such as caffeine, an H2antagonist (e.g., ranitidine), simethicone, aluminum or magnesiumhydroxide; a decongestant such as phenylephrine, phenylpropanolamine,pseudoephedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levo desoxy ephedrine; anantitussive such as codeine, hydrocodone, caramiphen, carbetapentane, ordextromethorphan; a diuretic; and a sedating or non sedatingantihistamine.

As noted, compounds and compositions of the present invention may beused in combination with other drugs that are used in the treatment,prevention, suppression or amelioration of the diseases or conditionsfor which compounds and compositions of the present invention areuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound or composition of the present invention. When a compound orcomposition of the present invention is used contemporaneously with oneor more other drugs, a pharmaceutical composition containing such otherdrugs in addition to the compound or composition of the presentinvention is preferred. Accordingly, the pharmaceutical compositions ofthe present invention include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to a compound orcomposition of the present invention. Examples of other therapeuticagents that may be combined with a compound or composition of thepresent invention, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: (a) VLA-4antagonists, (b) corticosteroids, such as beclomethasone,methylprednisolone, betamethasone, prednisone, prenisolone,dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone,salmeterol, salmeterol, salbutamol, formeterol; (c) immunosuppressantssuch as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus(FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil(CellCept®); (d) antihistamines (H1-histamine antagonists) such asbromopheniramine, chlorpheniramine, dexchloipheniramine, triprolidine,clemastine, diphenhydramine, diphenylpyraline, tripelennamine,hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine,cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non steroidal antiasthmatics (e.g., terbutaline, metaproterenol, fenoterol, isoetharine,albuterol, bitolterol and pirbuterol), theophylline, cromolyn sodium,atropine, ipratropium bromide, leukotriene antagonists (e.g.,zafmlukast, montelukast, pranlukast, iralukast, pobilukast andSKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005);(f) non steroidal anti-inflammatory agents (NSAIDs) such as propionicacid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, rniroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acidderivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetyl salicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h)inhibitors of phosphodiesterase type IV (PDE IV); (i) gold compoundssuch as auranofin and aurothioglucose, (j) etanercept (Enbrel®), (k)antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®),basiliximab (Simulect®) and infliximab (Remicade®), (1) otherantagonists of the chemokine receptors, especially CCR5, CXCR2, CXCR3,CCR2, CCR3, CCR4, CCR7, CX₃CR1 and CXCR6; (m) lubricants or emollientssuch as petrolatum and lanolin, (n) keratolytic agents (e.g.,tazarotene), (o) vitamin D₃ derivatives, e.g., calcipotriene orcalcipotriol (Dovonex®), (p) PUVA, (q) anthralin (Drithrocreme®), (r)etretinate (Tegison®) and isotretinoin and (s) multiple sclerosistherapeutic agents such as interferon β-1β (Betaseron®), interferon(β-1α (Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate(Capoxone®), a glucocorticoid (e.g., prednisolone) and cyclophosphamide(t) DMARDS such as methotrexate (u) other compounds such as5-aminosalicylic acid and prodrugs thereof, hydroxychloroquine;D-penicillamine; antimetabolites such as azathioprine, 6-mercaptopurineand methotrexate; DNA synthesis inhibitors such as hydroxyurea andmicrotubule disrupters such as colchicine. The weight ratio of thecompound of the present invention to the second active ingredient may bevaried and will depend upon the effective dose of each ingredient.Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with an NSAID theweight ratio of the compound of the present invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Method of Inducing Progenitor/Stem Cell Mobilization

Still further, the compounds and compositions of the present inventioncan be useful for mobilizing progenitor/stem cells and thus for treatingor ameliorating disorders or conditions for which progenitor/stem cellmobilization is efficacious or desirable, optionally using the compoundsof the present invention according to the procedures and protocols asdescribed in WO05/000333, incorporated herein by reference in itsentirety for all purposes. Conditions that may be ameliorated orotherwise benefited include, for example, hematopoietic disorders, suchas aplastic anemia, leukemias, drug-induced anemias, and hematopoieticdeficits from chemotherapy or radiation therapy. Still further, thecompounds and compositions of the invention can be used in enhancing thesuccess of transplantation during and following immunosuppressivetreatments as well as in effecting more efficient wound he Stillfurther, the compounds and compositions of the present invention can beuseful for mobilizing progenitor/stem cells and thus for treating orameliorating disorders or conditions for which progenitor/stem cellmobilization is efficacious or desirable, optionally using the compoundsof the present invention according to the procedures and protocols asdescribed in WO05/000333, incorporated herein by reference in itsentirety for all purposes. Conditions that may be ameliorated orotherwise benefited include, for example, hematopoietic disorders, suchas aplastic anemia, leukemias, drug-induced anemias, and hematopoieticdeficits from chemotherapy or radiation therapy. Still further, thecompounds and compositions of the invention can be used in enhancing thesuccess of transplantation during and following immunosuppressivetreatments as well as in effecting more efficient wound healing andtreatment of bacterial infections. Optionally, following administrationof the compounds of the invention, and following progenitor/stem cellmobilization, blood comprising the mobilized cells is collected andoptionally, the mobilized cells are purified and optionally expanded,and where desired, reintroduced into the same person or into a secondperson (e.g., a matched donor).

A number of different types of cells can be mobilized as desired. Insome embodiments, hematopoietic progenitor cells (HSCs) are mobilizedfollowing administration of the compounds or compositions of theinvention, and optionally harvested and purified from other bloodcomponents. Optionally, HSC mobilization is induced by administration ofat least one compound of the invention in conjunction with one or moreof granulocyte-colony stimulating factor (G-CSF) or AMD3100(1,1′-[1,4-Phenylenebis(methylene)] bis[1,4,8,11-tetraazacyclotetradecane] octohydrobromide dihydrate) orsalts, racemates, or isomers thereof.

In some embodiments, endothelial progenitor cells (EPCs) are mobilizedfollowing administration of the compounds or compositions of theinvention, and optionally harvest and purified from other bloodcomponents. Optionally, EPC mobilization is induced by administration ofat least one compound of the invention in conjunction with one or moreof vascular endothelial growth factor (VEGF), a VEGF agonist (includingbut not limited to a VEGF agonist antibody) or AMD3100 or salts,racemates, or isomers thereof.

In some embodiments, mesenchymal stem cells (MSCs) or stromal progenitorcells (SPCs) are mobilized following administration of the compounds orcompositions of the invention, and optionally harvest and purified fromother blood components. Optionally, such mobilization is induced byadministration of at least one compound of the invention in conjunctionwith one or more of G-CSF, VEGF, a VEGF agonist (including but notlimited to a VEGF agonist antibody), AMD3100, or salts, racemates, orisomers thereof.

For immobilizing progenitor or stem cells, an appropriate dosage levelwill generally be about 0.001 to 100 mg per kg patient body weight perday which can be administered in single or multiple doses. The compoundsmay be administered as a single dose, a dose over time, as in i.v., ortransdermal administration, or in multiple doses. The compounds of theinvention can also be used in ex vivo treatment protocols to preparecell cultures which are then used to replenish the blood cells of thesubject. Ex vivo treatment can be conducted on autologous cellsharvested from the peripheral blood or bone marrow or from allograftsfrom matched donors.

The present compounds can be combined with other compounds andcompositions that induce activation, proliferation or mobilization ofprogenitor/stem cells. In addition to those described above, theseinclude but are not limited to Fins-related tyrosine kinase 3 ligand(Flt3 ligand), interleukin 3 (IL-3), interleukin 7 (IL-7), interleukin20 (IL-20), Steel factor (SF) and granulocyte macrophagecolony-stimulating factor (GM-CSF) and may provide therapeutic utilitiesthat may require or benefit from treatment either before, after orsimultaneously with mobilization of progenitor/stem cells. Accordingly,combination methods and compositions are also a component of the presentinvention to prevent and treat the condition or disease of interest.Additionally, the compounds of the present invention can provide benefitin conditions in which disregulation of stem cell mobilization may playa role, such as heart disease and pulmonary hypertension.

Method of Diagnosing Diseases and Disorders Associated with CXCR7

Still further, the compounds and compositions of the present inventionare useful for the diagnosis of diseases and disorders associated withCXCR7. In particular, the compounds of the present invention can beprepared in a labeled form (e.g., radiolabeled) and used for thediagnosis of, for example, cancer. Labeled compounds of the presentinvention that bind to CXCR7 (e.g., antagonists or agonists) can be usedto determine levels of CXCR7 in a mammalian subject. In someembodiments, the CXCR7 modulators are administered to a subject havingcancer. In some cases, labeled compounds are administered to detectdeveloping cancers, e.g., carcinomas, gliomas, mesotheliomas, melanomas,lymphomas, leukemias, adenocarcinomas, breast cancer, ovarian cancer,cervical cancer, glioblastoma, leukemia, lymphoma, prostate cancer, andBurkitt's lymphoma, head and neck cancer, colon cancer, colorectalcancer, non-small cell lung cancer, small cell lung cancer, cancer ofthe esophagus, stomach cancer, pancreatic cancer, hepatobiliary cancer,cancer of the gallbladder, cancer of the small intestine, rectal cancer,kidney cancer, bladder cancer, prostate cancer, penile cancer, urethralcancer, testicular cancer, cervical cancer, vaginal cancer, uterinecancer, ovarian cancer, thyroid cancer, parathyroid cancer, adrenalcancer, pancreatic endocrine cancer, carcinoid cancer, bone cancer, skincancer, retinoblastomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma(see, CANCER: PRINCIPLES AND PRACTICE (DeVita, V. T. et al. eds 1997)for additional cancers); as well as brain and neuronal dysfunction, suchas Alzheimer's disease and multiple sclerosis; kidney dysfunction;rheumatoid arthritis; cardiac allograft rejection; atherosclerosis (andelevated cholesterol levels); asthma; glomerulonephritis; contactdermatitis; inflammatory bowel disease; colitis; psoriasis; reperfusioninjury; as well as other disorders and diseases described herein. Insome embodiments, the subject does not have Kaposi's sarcoma,multicentric Castleman's disease or AIDS-associated primary effusionlymphoma. Since CXCR7 is often expressed in cancer cells but notnon-cancer cells, it is typically desirable to administer antagonists ofCXCR7 to subjects at risk of having cancer.

A variety of imaging and detection methods can be used for the detectionof cancers. In some embodiments, direct methods are available toevaluate CXCR7 biodistribution in the body such as magnetic resonanceimaging (“MRI”), positron emission tomography (“PET”), and single photonemission computed tomography (“SPECT”). Each of these methods can detectthe distribution of a suitably labeled compound (generally as bound toCXCR7) within the body if that compound contains an atom with theappropriate nuclear properties. MRI detects paramagnetic nuclei; PET andSPECT detect the emission of particles from the decay of radionuclei.

For methods involving PET, it is necessary to incorporate an appropriatepositron-emitting radionuclide. There are relatively fewpositron-emitting isotopes that are suitable for labeling a therapeuticagent. The carbon isotope, ¹¹C, has been used for PET, but has a shorthalf-life of 20.5 minutes. Accordingly, the facilities for synthesis anduse are typically near to a cyclotron where the precursor ¹¹C startingmaterial is generated. Another useful isotope, ¹⁸F, has a half-life of110 minutes. This allows sufficient time for incorporation into aradiolabeled tracer, for purification and for administration into ahuman or animal subject. Other isotopes have even shorter half-lives.¹³N has a half-life of 10 minutes and ¹⁵O has an even shorter half-lifeof 2 minutes. The emissions of both are more energetic, however, thanthose of ¹¹C and PET studies have been carried out with these isotopes(see, Clinical Positron Emission Tomography, Mosby Year Book, 1992, K.F. Hubner, et al., Chapter 2).

SPECT imaging employs isotope tracers that are γ-emitters. While therange of useful isotopes is greater than for PET, imaging with SPECTprovides lower three-dimensional resolution. However, in some instances,SPECT is used to obtain clinically significant information aboutcompound binding, localization and clearance rates. One useful isotopefor SPECT imaging is ¹²³I, a γ-emitter with a 13.3 hour half life.Compounds labeled with ¹²³I can be shipped up to about 1000 miles fromthe manufacturing site, or the isotope itself can be transported foron-site synthesis. Eighty-five percent of the isotope's emissions are159 KeV photons, which are readily measured by SPECT instrumentationcurrently in use. Other halogen isotopes can serve for PET or SPECTimaging, or for conventional tracer labeling. These include ⁷⁵Br, ⁷⁶Br,⁷⁷Br and ⁸²Br as having usable half-lives and emission characteristics.

In view of the above, the present invention provides methods for imaginga tumor, organ, or tissue, said method comprising:

-   -   (a) administering to a subject in need of such imaging, a        radiolabeled or detectable form of a compound of Formula I; and    -   (b) detecting said compound to determine where said compound is        concentrated in said subject.

Additionally, the present invention provides methods for detectingelevated levels of CXCR7 in a sample, said method comprising:

-   -   (a) contacting a sample suspected of having elevated levels of        CXCR7 with a radiolabeled or detectable form of a compound of        Formula I;    -   (b) determining a level of compound that is bound to CXCR7        present in said sample to determine the level of CXCR7 present        in said sample; and    -   (c) comparing the level determined in step (b) with a control        sample to determine if elevated levels of CXCR7 are present in        said sample.

As with the treatment methods described herein, administration of thelabeled compounds can be by any of the routes normally used forintroducing a compound into ultimate contact with the tissue to beevaluated and is well known to those of skill in the art. Although morethan one route can be used to administer a particular composition, aparticular route can often provide a more immediate and more effectivediagnosis than another route.

Combination Therapies

Inhibitors of CXCR7 can be supplied alone or in conjunction with one ormore other drugs. Possible combination partners can include, e.g.,additional anti-angiogenic factors and/or chemotherapeutic agents (e.g.,cytotoxic agents) or radiation, a cancer vaccine, an immunomodulatoryagent, an anti-vascular agent, a signal transduction inhibitor, anantiproliferative agent, or an apoptosis inducer.

IV. Examples

The following examples are offered to illustrate, but not to limit theclaimed invention.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). ¹H-NMR spectrawere recorded on a Varian Mercury 400 MHz NMR spectrometer. Significantpeaks are provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge, followed by the relative abundance ofeach ion (in parenthesis). In the examples, a single m/e value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP 1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol at 0.1 mg/mL and 1 microlitre was infused with the deliverysolvent into the mass spectrometer, which scanned from 100 to 1500daltons. All compounds could be analyzed in the positive ESI mode, usingacetonitrile/water with 1% formic acid as the delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery system.

The following abbreviations are used in the Examples and throughout thedescription of the invention: rt, room temperature; HPLC, high pressureliquid chromatography; TFA, trifluoroacetic acid; LC-MSD, liquidchromatograph/mass selective detector; LC-MS, liquid chromatograph/massspectrometer; Pd₂dba₃, tris(dibenzylideneacetone) dipalladium; THF,tetrahydrofuran; DMF, dimethylformamide or N,N-dimethylformamide; DCM,dichloromethane; DMSO, dimethyl sulfoxide; TLC, thin-layerchromatography; KHMDS, potassium hexamethyldisilazane; ES, electrospray;sat., saturated.

Compounds within the scope of this invention can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisinvention, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1: Synthesis of ethyl1-(4-fluorophenyl)-1,2,4-triazole-3-carboxylate

4-Fluoroaniline (2.8 g, 26 mmol) was dissolved in 10% HCl and cooled to0° C. To this solution was carefully added NaNO₂ (1.8 g, 26 mmol)dissolved in 10 mL water. In a separate flask, NaOAc (13 g, 96 mmol),and water (25 mL) were added to a solution of ethyl isocyanoacetate (2.0g, 18 mmol) in methanol (80 mL). This solution was cooled to 0° C. andthe diazonium salt of 4-fluoroaniline was carefully added over thecourse of 15 minutes. Stirring was continued at 0° C. for an additional15 minutes, after which the flask was removed from the ice bath andstirring was continued for an additional 2 hours. The reaction mixturewas then added to 500 mL water and the resulting brown precipitate wascollected by filtration and dried in vacuo to obtain 3.8 g of thedesired ester (90% yield).

Example 2: Synthesis of 1-(4-fluorophenyl)-1,2,4-triazole-3-carboxylicacid

1.84 g of ethyl 1-(4-fluorophenyl)-1,2,4-triazole-3-carboxylate (7.83mmol) was suspended in a solution of 0.63 g of sodium hydroxide (2equiv.) in 110 mL of water. The mixture was vigorously stirred andslowly brought up to 50° C., whereupon all solids have dissolved. Thesolution was cooled down to r.t and diluted with water to a total volumeof 400 mL. 1.31 mL of concentrated HCl (2 equiv.) was added while themixture was vigorously stirred. The stirring was continued for 15minutes, letting all the solids to disperse evenly. The white solidswere filtered off and thoroughly washed on the funnel with 15 mL ofwater and then dried in a vacuum oven at 50° C. to obtain 1.6 g of theacid product as a white powder (99% yield).

Example 3: Synthesis of 1-(4-fluorophenyl)-1,2,4-triazole-3-acetylchloride

1.71 g (8.24 mmol) of 1-(4-fluorophenyl)-1,2,4-triazole-3-carboxylicacid was suspended in 15 mL of 1,2-dichloroethane and then 1.24 mL (12.4mmol) of oxalyl chloride was added dropwise at r.t., followed by 1.6 μL(0.021 mmol) of DMF. The mixture was stirred at r.t. and then slowlybrought up to 60° C. Another 1.6 μL portion of DMF was added, resultingin full dissolution of the material after 5 minutes. The solution wasconcentrated in vacuo to obtain 1.86 g of the desired product as a lightyellow solid (100% yield). The product was used in subsequent stepswithout purification.

Example 4: Synthesis of ethyl1-(4-Chloro-3-fluorophenyl)pyrazole-3-carboxylate

A 50 mL of flask was charged with 3.00 g of4-chloro-3-fluorobenzenebromide (15 mmol), 1.40 g of ethyl1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g ofK₂CO₃ (3.3 mmol) and 0.9 mL of trans-N,N′-dimethylcyclohexayldiamine(2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. Afterthe mixture was cooled down to room temperature, it was diluted with 200mL EtOAc and then was washed with water (2×50 mL), brine (2×50 mL). Theorganics was dried over MgSO₄ and concentrated under reduced pressure.The residue was purified via flash column chromatography on silica gel(0-25% EtOAc in hexanes) to get the desired product (1.2 g, 50%).

Example 5: Synthesis of 1-(4-chloro-3-fluorophenyl)pyrazole-3-carboxylicacid

To a solution of ethyl 1-(4-chloro-3-fluorophenyl)pyrazole-3-carboxylate(268 mg, 1 mmol) in THF was added 3.0 mL of 1.0M of LiOH (3.0 mmol). Theresulting mixture was stirred at room temperature for 3 h at which time1.0 M of HCl was added to adjust pH to 1.0. The organics were extractedwith EtOAc (2×100 mL), followed by drying over MgSO₄ and concentratedunder reduced pressure to give a white solid (230 mg, 96%), which wasused for next step without further purification.

Example 6: Synthesis of ethyl 1-(4-chlorophenyl)pyrazole-3-carboxylate

A 50 mL of flask was charged with 2.87 g of 4-chlorobenzenebromide (15mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg ofCuI (2.0 mmol), 4.5 g of K₂CO₃ (3.3 mmol) and 0.9 mL oftrans-N,N′-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixturewas stirred at 140° C. for 3 h. After the mixture was cooled down toroom temperature, it was diluted with 200 mL EtOAc and then was washedwith water (2×50 mL) and brine (2×50 mL). The organics were dried overMgSO₄ and concentrated under reduced pressure. The residued was purifiedvia flash column chromatography on silica gel (0-25% EtOAc in hexanes)to get the desired product (1.25 g, 50%).

Example 7: Synthesis of 1-(4-chlorophenyl)pyrazole-3-carboxylic acid

To a solution of ethyl 1-(4-chlorophenyl)pyrazole-3-carboxylate (250 mg,1 mmol) in THF was added 3.0 mL of 1.0 M of LiOH (3.0 mmol). Theresulting mixture was stirred at room temperature for 3 h at which time1.0 M HCl was added to adjust the pH to 1.0. The organics were extractedwith EtOAc (2×100 mL), dried over MgSO₄, and concentrated under reducedpressure to give a white solid (213 mg, 96%), which was used for nextstep without further purification.

Example 8: Synthesis of ethyl 1-(3-fluorophenyl)pyrazole-3-carboxylate

A 50 mL of flask was charged with 2.62 g of 3-fluorobenzenebromide (15mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg ofCuI (2.0 mmol), 4.5 g of K₂CO₃ (3.3 mmol) and 0.9 mL oftrans-N,N′-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixturewas stirred at 140° C. for 3 h. After the mixture was cooled down toroom temperature, it was diluted with 200 mL EtOAc and then was washedwith water (2×50 mL), and brine (2×50 mL). The organics were dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedvia flash column chromatography on silica gel (0-25% EtOAc in hexanes)to give the desired product (1.17 g, 50%).

Example 9: Synthesis of 1-(3-fluorophenyl)pyrazole-3-carboxylic acid

To a solution of ethyl 1-(3-fluorophenyl)pyrazole-3-carboxylate (234 mg,1 mmol) in THF was added 3.0 mL of 1.0M of LiOH (3.0 mmol). Theresulting mixture was stirred at room temperature for 3 h and then 1.0 Mof HCl was added to adjust pH to 1.0. The organics were extracted withEtOAc (2×100 mL), followed by drying over MgSO₄ and concentrated underreduced pressure to give a white solid (198 mg, 96%), which was used fornext step without further purification.

Example 10: Synthesis of ethyl1-(4-fluorophenyl)-1,2,4-triazole-5-methyl-3-carboxylate

4-Fluorohydrazine hydrochloride (12.8 g, 7.7 mmol) and ethyl thiooxamte(10 g, 7.7 mmol) was suspended in water (80 ml) and then the mixture wascooled to 0° C. To this mixture was dropwise added triethylamine (10.77ml, 7.7 mmol). The resulting mixture was stirred at room temperature for2 hr. The solid as filtered was then washed with water (2×200 ml) to geta yellow solid (13.8 g, 6.1 mmol). 11.25 g of this yellow solid (50mmol) was dissolved in EtOH (50 ml) and 4 M HCl (0.5 ml) followed by theaddition of triethyl orthoacetate (8.9 g, 55 mmol). The resultingmixture was heated at 80° C. for 2 h and the solid (10 g, 85%) wascollected after it was cooled own to room temperature.

Example 11: Synthesis of1-(4-fluorophenyl)-1,2,4-triazole-5-methyl-3-carboxylic acid

1.94 g of ethyl 1-(4-fluorophenyl)-1,2,4-triazole-5-methyl-3-carboxylate(7.83 mmol) was suspended in a solution of 0.63 g of sodium hydroxide (2equiv.) in 110 mL of water. The mixture was vigorously stirred andslowly brought up to 50° C., whereupon all solids had dissolved. Thesolution was cooled down to rt and diluted with water to a total volumeof 400 mL. 1.31 mL of concentrated HCl (2 equiv.) was added while themixture was vigorously stirred. The stirring was continued for 15minutes. The white solids were then filtered off and thoroughly washedwith 15 mL of, then dried in a vacuum oven at 50° C. to obtain 1.7 g ofthe desired acid product as a white powder (99% yield).

Example 12: Synthesis of ethyl 2-pyrrolidinethiazole-4-carboxylate

A mixture of ethyl 2-chlorothiazole-4-carboxylate (500 mg, 2.6 mmol),pyrrolidine (210 mg, 2.98 mmol) and diethylisopropyl amine (1 mL) inp-dioxane (5 mL) was heated to 60° C. for 2 h. After cooling to roomtemperature, the solution was concentrated in vacuo and the residuepurified by flash chromatography (SiO₂, 2 to 5% MeOH in CH₂Cl₂ aseluent) to give the desired compound as a foam (400 mg, 68% yield, whichwas used directly for the next step). MS: (ES) m/z 227.1 (M+H⁺).

Example 13: Synthesis of 2-pyrrolidinethiazole-4-carboxylic acid

To the mixture of the above ester (400 mg, 1.8 mmol), MeOH (3 mL), THF(5 mL) and DI H₂O (2 mL) was added LiOH monohydrate (210 mg, 5 mmol).The resulting mixture was stirred at room temperature overnight. Themixture was diluted with ice-water, pH adjusted to pH 3 with 1 N HCl,and extracted with 20% MeOH in CH₂Cl₂. The organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo to give the desiredcompound as an off-white solid (300 mg, 89% yield, which was useddirectly for the next step). MS: (ES) m/z 199.1 (M+H⁺).

Example 14: Synthesis of2-(4-hydroxy-piperidin-1-yl)-thiazole-4-carboxylic acid

a) A flask was charged 4-hydroxypiperidine (236 mg, 2.33 mmol), ethyl2-bromothiazole-4-carboxylate (500 mg, 2.12 mmol), K₂CO₃ (879 mg, 6.36mmol), and N-methylpyrrolidine (3.5 mL). The reaction mixture was heatedto 90° C. and stirred overnight. The reaction was then diluted withEtOAc (30 mL) and washed with water (5×30 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The crude material waspurified on silica gel (95:5-20:80 hexanes:EtOAc) to give the productmixed with 2 equivalents of N-methylpyrrolidine (883 mg) as a clearcolorless oil.

b) The 2-(4-hydroxy-piperidin-1-yl)-thiazole-4-carboxylic acid ethylester mixture from step a was dissolved in MeOH (10 mL). To this wasadded NaOH (2 M, 5.00 mL). The reaction mixture was stirred overnight,then diluted 1M NaHSO₄ (30 mL). This solution was extracted with EtOAc(3×50 mL), and the combined organic layers were dried over Na₂SO₄,filtered, and concentrated to give the product (433 mg, 1.90 mmol, 90%)as a white solid.

Example 15: Synthesis of 2-(pyrrolidin-1-yl)thiazole-4-carboxylic acid

a) A mixture of ethyl 2-chlorothiazole-4-carboxylate (500 mg, 2.6 mmol),pyrrolidine (210 mg, 2.98 mmol) and diethylisopropyl amine (1 mL) inp-dioxane (5 mL) was heated to 60° C. for 2 h. After cooling to roomtemperature, the solvent was concentrated in vacuo and the residuepurified by flash chromatography (SiO₂, 2 to 5% MeOH in CH₂Cl₂ aseluent) to give the desired compound as a foam (400 mg, 68% yield, whichwas used directly for the next step). MS: (ES) m/z 227.1 (M+H⁺).

b) To the mixture of the above ester (400 mg, 1.8 mmol), MeOH (3 mL),THF (5 mL) and DI H₂O (2 mL) was added LiOH monohydrate (210 mg, 5mmol). The resulting mixture was stirred at room temperature overnight.The mixture was diluted with ice-water, pH was adjusted to 3 with 1 NHCl, and the solution was extracted with 20% MeOH in CH₂Cl₂. The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo give thedesired compound as an off-white solid (300 mg, 89% yield, which wasused directly for the next step). MS: (ES) m/z 199.1 (M+H⁺).

Example 16: Synthesis of methyl1-(o-fluorophenyl)-1,2,4-triazole-3-carboxylate

a) To a solution of methyl 1,2,4-triazole-3-carboxylate (1.0 g, 7.9mmol) in 10 mL DMF was added o-fluorophenylboronic acid (1.1 g, 7.9mmol), Cu(OAc)₂ (1.6 g, 8.8 mmol), and pyridine (0.70 mL, 8.7 mmol). Themixture was placed in a 90° C. oil bath and stirred vigorously for 3.5hours. Afterward the mixture was diluted with 100 mL EtOAc, filtered,and washed with 1:3 v/v conc. NH₄OH-saturated NH₄Cl. After removal ofsolvent under reduced pressure, the residue was purified by flashchromatography (SiO₂, 20-80% EtOAc/hexanes) to obtain 280 mg of whitepowder (16% yield).

b) To a solution of the ester from step a (280 mg, 1.3 mmol) dissolvedin 4 mL MeOH was added 2.5 mL of 1.0 M NaOH. After stirring 15 minutes,6.0 m HCl was added (0.42 mmol, 2.5 mmol), MeOH was removed underreduced pressure, and the white precipitate was collected by filtrationand dried in vacuo to obtain 150 mg of the desired acid (57% yield).

Example 17: Synthesis of 1-(o-tolyl)-1,2,4-triazole-3-carboxylic acid

To a solution of ethyl 1-(o-tolyl)-1,2,4-triazole-3-carboxylate (400 mg,1.7 mmol) in 3 mL THF was added 4 M LiOH (2 mL, 8 mmol) followed by 3 mLof MeOH. The reaction mixture was stirred at 50° C. for 5 minutes, afterwhich the pH was adjusted to 4 with the addition of conc. HCl. Afterextraction, drying (MgSO₄), filtration and drying under reducedpressure, 43 mg of residue was recovered (12%) and used in thesubsequent step without further purification.

Example 18: Synthesis of 1-(p-fluorophenyl)-1,2,4-triazole-3-carboxylicacid

4-Fluoroaniline (2.8 g, 26 mmol) was dissolved in 10% HCl and cooled to0° C. To this solution was carefully added NaNO₂ (1.8 g, 26 mmol)dissolved in 10 mL water. In a separate flask, NaOAc (13 g, 96 mmol),and water (25 mL) were added to a solution of ethyl isocyanoacetate (2.0g, 18 mmol) in methanol (80 mL). This solution was cooled to 0° C. andthe diazonium salt of 4-fluoroaniline was carefully added over thecourse of 15 minutes. Stirring was continued at 0° C. for an additional15 minutes, after which the flask was removed from the ice bath andstirring was continued for an additional 2 hours. The reaction mixturewas then added to 500 mL water and the resulting brown precipitate wascollected by filtration and dried in vacuo to obtain 3.8 g of thedesired ester (90% yield).

Example 19: Synthesis ofN-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-2-phenyl-thiazole-4-carboxamide

a) Ethyl 3-methyl-1H-pyrrole-2-carboxylate (2.45 g, 16.0 mmol) wasdissolved in a mixture of 8 mL of NMP and 2-bromo-1,1-diethoxyethane(3.23 mL, 20.8 mmol). 60% Sodium hydride (0.77 g, 19.2 mmol) was addedportionwise at rt. The resulting solution was heated to 130° C. for 5hours and then cooled down to rt. The solution was then diluted with 100mL of water and the resulting mixture was extracted with one 100 mLportion of MTBE. The organic layer was evaporated in vacuo and purifiedvia flash chromatography (SiO₂, 10-40% EtOAc/hexanes) to yield 1.90 g ofthe desired compound as a colorless oil (44% yield).

b) 1.90 g (7.06 mmol) Of ethyl1-(2,2-diethoxyethyl)-3-methyl-1H-pyrrole-2-carboxylate (prepared instep a above) was dissolved in 40 mL of ethanol-water mixture (1:1).Following the addition of 1.48 g (35.3 mmol) of lithium hydroxidemonohydrate, the mixture was heated to 75° C. for 8 hours. Aftercooling, the majority of the ethanol was evaporated in vacuo. Theresulting solution was diluted with 30 mL of water and neutralized with2.33 g of acetic acid (38.8 mmol), then extracted with two 30 mLportions of dichloromethane. The organic phase was dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to yield 1.68 gof a colorless solid (99% yield).

c) 1.68 g (6.97 mmol) of1-(2,2-diethoxyethyl)-3-methyl-1H-pyrrole-2-carboxylic acid (prepared instep b above) was dissolved in a mixture of 15 mL NMP and 45 mL of a 0.5M solution of ammonia gas in dioxane. 3.18 g of HATU (8.36 mmol) wasadded and the mixture was stirred overnight at rt. To this mixture 10 mLof NMP was added and the dioxane was evaporated in vacuo. Anotherportion of HATU was added (1.59 g, 4.18 mmol) and ammonia gas wasbubbled through the mixture and until no more reaction progress wasobserved. The mixture was then diluted with 300 mL of brine andextracted with one 150 mL portion of MTBE. The organic layer wasevaporated in vacuo and purified via flash chromatography (SiO₂, 20-100%EtOAc/hexanes) to give 1.26 g of the desired compound as a colorless oil(75% yield).

d) 1.25 g (5.21 mmol) of1-(2,2-diethoxyethyl)-3-methyl-1H-pyrrole-2-carboxamide (prepared instep c above) was dissolved in 30 mL of glacial acetic acid and heatedto 105° C. for 4 hours, then evaporated to dryness in vacuo. The residuewas dissolved in 25 mL of hot dichloromethane, then diluted with 30 mLof hexanes while evaporating most of the dichloromethane. The solidswere filtered off, washed with 5 mL of hexanes, and dried to give 730 mgof the pure desired compound as a tan powder (95% yield).

e) 725 mg (4.90 mmol) of 8-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one(prepared in step d above) was suspended in 7 mL of phosphoryl chlorideand stirred at r.t. overnight, followed by heating to 35° C. for 4hours. The resulting solution was then evaporated to dryness in vacuo.The residue was taken up in a mixture of 10 mL of dichloromethane and 10mL of aqueous sodium bicarbonate and stirred until gas evolution hadceased. The separated organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was dissolvedin 9 mL of hot n-heptane. The solution was decanted off the insolubleblack tars and concentrated in vacuo to give 774 mg of the desiredproduct as an off-white solid (95% yield).

f) 646 mg (3.87 mmol) Of 1-chloro-8-methyl-pyrrolo[1,2-a]pyrazine(prepared in step e above), 2.16 g (11.6 mmol) of(S)-3-(Boc-amino)pyrrolidine, 1 mL of N,N-diisopropylethylamine and 1 mLof NMP were combined and heated to 120° C. for 1 hour. The mixture wascooled down, diluted with 50 mL of water and extracted with three 50 mLportions of ethyl acetate. Solid sodium bicarbonate was added to theaqueous layer and it was extracted again with 50 mL of ethyl acetate.The combined organic layers were washed with aqueous sodium bicarbonate,evaporated in vacuo and purified using flash chromatography (SiO₂,20-60% EtOAc/hexanes) to yield 872 mg of the desired compound as acolorless oil (71% yield).

g) 872 mg (2.75 mmol) of tert-butylN-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]carbamate(prepared in step f above) was dissolved in 3.5 mL of dioxane. To thissolution 3.5 mL of a hydrogen chloride solution in dioxane (4 M) wasadded and the mixture was stirred at 60° C. for 1 hour, during whichprecipitation of colorless solids was observed. The volatiles wereremoved in vacuo to give 739 mg of the desired compound without furtherpurification (93% yield).

h) 39 mg (0.135 mmol) of(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (prepared in step g above) and 28 mg (0.135 mmol) of2-phenylthiazole-4-carboxylic acid were dissolved in 0.5 mL of NMP. Tothis mixture were added 77 mg (0.203 mmol) of HATU and 0.117 mL (0.675mmol) of N,N-diisopropylethylamine. The mixture was stirred at r.t. for1 hour, then diluted with 3 mL of DMSO and injected directly onto areverse-phase semi-preparative HPLC system (5-60% acetonitrile/water,0.1% TFA). Pure fractions were concentrated in vacuo to give 66 mg ofthe desired product as a TFA salt (95% yield). ¹H NMR (400 MHz, DMSO) δ11.28 (s, 1H), 8.82 (d, J=7.0 Hz, 1H), 8.33 (s, 1H), 8.04-8.01 (m, 2H),7.82 (m, 2H), 7.54-7.50 (m, 3H), 6.86 (d, J=5.5 Hz, 1H), 6.76 (d, J=2.2Hz, 1H), 4.75-4.65 (m, 1H), 4.20-3.60 (m, 4H), 2.48 (s, 3H), 2.40-2.20(m, 2H); MS: (ES) m/z calculated for C₂₂H₂₁N₅OS [M+H]⁺ 404.2, found 404.

Example 20: Synthesis of1-(4-chlorophenyl)-N-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]pyrazole-3-carboxamide

40 mg (0.138 mmol) of(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride and 31 mg (0.138 mmol) of1-(4-chlorophenyl)pyrazole-3-carboxylic acid were dissolved in 0.5 mL ofNMP. To this mixture were added 79 mg (0.207 mmol) of HATU and 0.120 mL(0.690 mmol) of N,N-diisopropylethylamine. The mixture was stirred at rtfor 1 hour, then diluted with 3 mL of DMSO and injected directly onto areverse-phase semi-preparative HPLC system (5-60% acetonitrile/water,0.1% TFA). Pure fractions were concentrated in vacuo, dissolved in 1 mLof methanol and passed through a bicarbonate resin cartridge (PL-HCO3 MPSPE 500 mg/6 mL). To the resulting solution 15 μL of concentratedhydrochloric acid was added and the volatiles were removed in vacuo togive 49 mg of the desired product as an HCl salt (78% yield). ¹H NMR(400 MHz, DMSO) δ 11.38 (s, 1H), 8.78 (d, J=7.0 Hz, 1H), 8.59 (d, J=3.0Hz, 1H), 7.95 (d, J=7.0, 2H), 7.81 (m, 2H), 7.61 (d, J=8.8 Hz, 2H), 6.92(s, 1H), 6.85 (d, J=5.5 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 4.70-4.65 (m,1H), 4.18-3.80 (m, 4H), 2.48 (s, 3H), 2.38-2.18 (m, 2H); MS: (ES) m/zcalculated for C₂₂H₂₁ClN₆O [M+H]⁺ 421.2, found 421.

Example 21: Synthesis of6-methyl-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]quinazoline-2-carboxamide

43 mg (0.156 mmol) of(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride and33 mg (0.156 mmol) of 6-methylquinazoline-2-carboxylic acidhydrochloride were dissolved in 0.4 mL of NMP. To this mixture was added85 mg (0.224 mmol) of HATU and 155 μL (0.892 mmol) ofN,N-diisopropylethylamine. The mixture was stirred at rt for 30 minutes,then diluted with 3 mL of DMSO and injected directly onto areverse-phase semi-preparative HPLC system (5-40% acetonitrile/water,0.1% TFA). Pure fractions were concentrated in vacuo to give 39 mg ofthe desired product as a TFA salt (51% yield). ¹H NMR (400 MHz, CD₃OD) δ9.49 (s, 1H), 8.04 (d, J=9.1 Hz, 1H), 7.93 (d, J=6.9 Hz, 2H), 7.75 (d,J=1.5 Hz, 1H), 7.70 (d, J=5.9 Hz, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 6.85(d, J=5.5 Hz, 1H), 5.00-3.70 (m, 5H), 3.30 (s, 3H), 2.60-2.30 (m, 2H);MS: (ES) m/z calculated for C₂₁H₂₀N₆O [M+H]⁺ 373.2, found 373.

Example 22: Synthesis of1-(4-chlorophenyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamide.trifluoroacetatesalt

To a solution of 1-(4-chlorophenyl)pyrazole-3-carboxylic acid (49 mg,0.22 mmol) in 0.80 mL DMSO was added(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride (74mg, 0.27 mmol), followed by triethylamine (0.12 mL, 0.86 mmol) and HATU(92 mg, 0.24 mmol). After 1.5 hours the reaction mixture was dilutedwith 1 mL water, filtered, purified by reverse phase preparative HPLC(22-36% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the product. ¹H NMR (400 MHz, CD₃OD) δ 8.76 (d,J=6.2 Hz, 1H), 8.31 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.77 (d, J=2.5 Hz,1H), 7.72 (d, J=5.5 Hz, 1H), 7.57 (d, J=5.5 Hz, 1H), 7.50 (d, J=8.8 Hz,2H), 6.96 (d, J=2.5, 1H), 6.93 (dd, J=2.6, 7.0 Hz, 1H), 6.84 (d, J=5.9Hz, 1H), 4.95-4.80 (m, 1H), 4.70-3.70 (br, 4H), 2.60-2.30 (m, 2H). MS:(ES) 407.2 (M+H⁺).

Example 23: Synthesis of1-(o-tolyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamide.trifluoroacetatesalt

To a solution of 1-(o-tolyl)pyrazole-3-carboxylic acid (35 mg, 0.17mmol) in 0.80 mL DMSO was added added(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride (46mg, 0.17 mmol), followed by triethylamine (0.10 mL, 0.70 mmol) and HATU(80 mg, 0.21 mmol). After 1 hour the reaction mixture was diluted indichloromethane (70 mL), washed with water (20 mL) and concentratedunder reduced pressure. The residue was purified by reverse phasepreparative HPLC (20-40% gradient of CH₃CN/H₂O with 0.1% TFA modifier)and dried (lyophilizer) to give the desired compound. ¹H NMR (400 MHz,CD₃OD) δ 8.62 (d, J=5.9 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.75 (s, 1H),7.70 (d, J=5.9 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H), 7.40-7.25 (m, 4H), 6.94(d, J=2.2 Hz, 1H), 6.91 (dd, J=2.6, 4.4 Hz, 1H), 6.82 (d, J=5.5 Hz, 1H),4.95-3.65 (br, 5H), 2.58-2.30 (m, 2H), 2.20 (s, 3H). MS: (ES) 387.2(M+H⁺).

Example 24: Synthesis of1-(o-tolyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

To a solution of 1-(o-tolyl)-1,2,4-triazole-3-carboxylic acid (43 mg,0.21 mmol) in 1 mL DMSO was added(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride (60mg, 0.22 mmol), followed by triethylamine (0.12 mL, 0.89 mmol) and HATU(80 mg, 0.21 mmol). After 20 minutes, the reaction mixture was quenchedwith 10 mL water and extracted with dichloromethane. The organic layerwas separated and concentrated under reduced pressure. The residue waspurified by reverse phase preparative HPLC (20-40% gradient of CH₃CN/H₂Owith 0.1% TFA modifier) and dried (lyophilizer) to give 20 mg of thedesired compound (19% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.73 (s, 1H),7.76 (d, J=2.6 Hz, 1H), 7.70 (d, J=5.5 Hz, 1H), 7.55 (d, J=4.0 Hz, 1H),7.50-7.32 (m, 4H), 6.92 (dd, J=2.5, 4.4 Hz, 1H), 6.83 (d, J=5.9 Hz, 1H),4.95-4.80 (m, 1H), 4.70-3.70 (br, 5H), 2.60-2.30 (m, 2H), 2.22 (s, 3H).MS. (ES) 388.2 (M+H⁺).

Example 25: Synthesis ofN-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-5-phenyl-pyrimidine-2-carboxamide.trifluoroacetatesalt

a) To a solution of 5-bromopyrimidine-2-carboxylic acid (41 mg, 0.20mmol) in 0.80 mL DMSO was added(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (61 mg, 0.21 mmol), followed by triethylamine (0.12 mL,0.86 mmol) and HATU (81 mg, 0.21 mmol). After 20 minutes, the reactionmixture was quenched with 10 mL water and extracted withdichloromethane. The organic layer was separated and concentrated underreduced pressure. The residue was purified by flash chromatography(SiO₂, 2% 7 M NH₃ in MeOH/dichloromethane). MS: (ES) 402.2 (M+H⁺).

b) In a 4 mL vial, the product from step a was combined withphenylboronic acid (24 mg, 0.2 mmol), Pd(PPh₃)₄ (23 mg, 0.020 mmol),degassed toluene (2 mL), and degassed 2 M K₂CO₃ (0.3 mL, 0.6 mmol). Thevial was sealed and the reaction mixture was stirred on a preheated hotplate at 100° C. for 1 hour. The reaction mixture was concentrated underreduced pressure and purified by reverse phase preparative HPLC (20-30%gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried (lyophilizer) togive the desired product. ¹H NMR (400 MHz, CD₃OD) δ 9.18 (s, 2H), 7.77(d, J=7.0 Hz, 2H), 7.67 (d, J=5.9 Hz, 2H), 7.57-7.48 (m, 3H), 6.76-6.72(m, 2H), 4.95-4.80 (m, 1H), 4.32-4.24 (m, 1H), 4.10-3.90 (m, 3H), 2.64(s, 3H), 2.50-2.35 (m, 2H). MS: (ES) 389.2 (M+H⁺).

Example 26: Synthesis ofN-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-1-(o-tolyl)pyrazole-3-carboxamide.trifluoroacetatesalt

To a solution of 1-(o-tolyl)pyrazole-3-carboxylic acid (27 mg, 0.13mmol) in 0.60 mL DMSO was added(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (39 mg, 0.13 mmol), followed by triethylamine (0.080 mL,0.58 mmol) and HATU (53 mg, 0.14 mmol). After 15 minutes, acetic acid(0.060 mL, 1 mmol) was added to the reaction mixture, followed by CH₃OH(0.60 mL) and water (0.70 mL). The mixture was filtered and purified byreverse phase preparative HPLC (20-40% gradient of CH₃CN/H₂O with 0.1%TFA modifier) and dried (lyophilizer) to give the desired product. ¹HNMR (400 MHz, CD₃OD) δ 7.87 (s, 1H), 7.64 (m, 2H), 7.40-7.28 (m, 4H),6.93 (s, 1H), 6.74-6.70 (m, 2H), 4.80-4.70 (m, 1H), 4.30-4.20 (m, 1H),4.10-3.85 (m, 3H), 2.61 (s, 3H), 2.50-2.35 (m, 2H), 2.20 (s, 3H). MS:(ES) 401.2 (M+H⁺).

Example 27: Synthesis ofN-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-2-phenyl-oxazole-4-carboxamide.trifluoroacetatesalt

To a solution of 2-phenyloxazole-4-carboxylic acid (24 mg, 0.13 mmol) in0.5 mL DMSO was added(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (41 mg, 0.14 mmol), followed by triethylamine (0.080 mL,0.58 mmol) and HATU (53 mg, 0.14 mmol). After 15 minutes, acetic acid(0.060 mL, 1 mmol) was added to the reaction mixture, followed by CH₃OH(0.60 mL) and water (0.70 mL). The mixture was filtered and purified byreverse phase preparative HPLC (20-40% gradient of CH₃CN/H₂O with 0.1%TFA modifier) and dried (lyophilizer) to give the desired product. ¹HNMR (400 MHz, CD₃OD) δ 8.72 (d, J=8.1 Hz, 1H), 8.45 (s, 1H), 8.06 (d,J=8.1 Hz, 2H), 7.67 (d, J=5.5 Hz, 2H), 7.52 (m, 3H), 6.76-6.73 (m, 2H),4.85-4.75 (m, 1H), 4.30-4.22 (m, 1H), 4.10-3.90 (m, 3H), 2.64 (s, 3H),2.55-2.35 (m, 2H). MS: (ES) 388.2 (M+H⁺).

Example 28: Synthesis of5-phenyl-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrimidine-2-carboxamide.trifluoroacetatesalt

a) To a solution of 5-bromopyrimidine-2-carboxylic acid (120 mg, 0.59mmol) in 2.0 mL DMSO was added(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride (160mg, 0.58 mmol), followed by triethylamine (0.30 mL, 2.2 mmol) and HATU(228 mg, 0.60 mmol). After stirring overnight, the reaction mixture wasquenched with 10 mL water and extracted with dichloromethane. Theorganic layer was separated and concentrated under reduced pressure. Theresidue was purified by flash chromatography (SiO₂, 2% 7 M NH₃ inMeOH/dichloromethane). MS: (ES) 388.2 (M+H⁺).

b) In a 4 mL vial, the product from step a (80 mg, 0.21 mmol) wascombined with phenylboronic acid (29 mg, 0.24 mmol), Pd(PPh₃)₄ (25 mg,0.021 mmol), degassed toluene (2 mL), and degassed 2 M K₂CO₃ (0.35 mL,0.7 mmol). The vial was sealed and the reaction mixture was stirred on apreheated hot plate at 100° C. for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and purified by reverse phasepreparative HPLC (20-40% gradient of CH₃CN/H₂O with 0.1% TFA modifier)and dried (lyophilizer) to give the desired product. ¹H NMR (400 MHz,CD₃OD) δ 9.42 (d, J=7.0 Hz, 0.8H), 9.18 (s, 2H), 7.77-7.70 (m, 4H),7.58-7.48 (m, 4H), 6.93 (dd, J=2.6, 4.4 Hz, 1H), 6.85 (d, J=5.5 Hz, 1H),5.00-3.65 (br, 5H), 2.65-2.40 (m, 2H). MS: (ES) 385.1 (M+H⁺).

Example 29: Synthesis of5-phenyl-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]-4H-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

To a solution of sodium 5-phenyl-4H-1,2,4-triazole-3-carboxylate (50 mg,0.24 mmol) in 0.70 mL DMSO was added(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride (80mg, 0.29 mmol), followed by triethylamine (0.14 mL, 1.0 mmol) and HATU(105 mg, 0.28 mmol). After stirring the reaction mixture overnight, itwas purified directly by reverse phase preparative HPLC (20-30% gradientof CH₃CN/H₂O with 0.1% TFA modifier) and dried (lyophilizer) to give thedesired product. ¹H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.05 (d, J=7.0Hz, 2H), 7.91 (s, 1H), 7.84 (d, J=4.4 Hz, 1H), 7.60-7.40 (m, 4H),7.00-6.90 (m, 2H), 4.85-3.50 (br, 5H), 2.45-2.20 (m, 2H). MS: (ES) 374.2(M+H⁺).

Example 30: Synthesis of5-(dimethylamino)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrimidine-2-carboxamide.trifluoroacetatesalt

In a 4 mL vial,4-bromo-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]benzamide(57 mg, 0.15 mmol) was combined withtris(dibenzylideneacetone)dipalladium (26 mg, 0.023 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (“X-Phos”, 49 mg,0.10 mmol), Cs₂CO₃ (250 mg, 0.77 mmol), degassed toluene (1.0 mL), and 2M dimethylamine in THF (1 mL, 2 mmol). The vial was sealed and thereaction mixture was stirred for 22 hours at 100° C. It was adsorbedonto silica gel and purified by flash chromatography (SiO₂, 2-5% 7 M NH₃in MeOH/dichloromethane), followed by reverse phase preparative HPLC(20-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the desired product. ¹H NMR (400 MHz, CD₃OD) δ8.27 (s, 2H), 7.75 (t, J=1.1, 1H), 7.70 (d, J=5.5, 1H), 7.55 (s, 1H),6.91 (dt, J=1.8, 2.6 Hz, 1H), 6.83 (d, J=5.5 Hz, 1H), 5.00-4.80 (m, 1H),4.65-3.70 (br, 4H), 3.10 (s, 6H), 2.60-2.30 (m, 2H). MS: (ES) 352.2(M+H⁺).

Example 31: Synthesis of5-(1-hydroxyethyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrimidine-2-carboxamide.trifluoroacetatesalt

a) To a 15 mL heavy-walled pressure vessel was added4-bromo-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]benzamide(289 mg, 0.747 mmol), tri-n-butyl(1-ethoxyvinyl)tin (0.35 mL, 1.0 mmol),dichlorobis(triphenylphosphine)palladium (30 mg, 0.042 mmol), anddegassed dioxane (4 mL). The vessel was sealed and immersed into apreheated (140° C.) oil bath. After 25 minutes, the vessel was removedfrom the oil bath, allowed to cool to room temperature, and treated with6 M HCl (0.40 mL, 2.4 mmol), and stirred overnight. The reaction mixturewas diluted with 200 mL dichloromethane and 20 mL water. The organiclayer was separated and set aside, while the aqueous phase was basifiedwith NaOH and extracted with dichloromethane. The combined organiclayers were concentrated under reduced pressure and the remainingresidue was purified by flash chromatography (SiO₂; 2-5%CH₃OH/dichloromethane) to obtain 209 mg of the desired compound (80%yield). MS: (ES) 351.2 (M+H⁺).

b) The ketone prepared in step a (56 mg, 0.16 mmol) was dissolved in 5mL MeOH and cooled to 0° C. on an ice bath. Sodium borohydride (7.2 mg,0.19 mmol) was added, and the reaction was stirred for 20 minutes at 0°C. The reaction was quenched with 6 M HCl, concentrated under reducedpressure, and directly purified by reverse phase preparative HPLC(20-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the desired compound. ¹H NMR (400 MHz, CD₃OD) δ8.93 (s, 2H), 7.79 (dd, J=1.2, 2.7 Hz, 1H), 7.74 (d, J=5.9 Hz, 1H), 7.58(d, J=3.5 Hz, 1H), 6.94 (dd, J=2.7, 5.7 Hz, 1H), 6.87 (d, J=5.9 Hz, 1H),5.02-4.95 (q, J=6.6 Hz, 1H), 4.80-3.60 (br, 5H), 2.62-2.38 (m, 2H), 1.53(d, J=6.6 Hz, 3H). MS: (ES) 353.2 (M+H⁺).

Example 32: Synthesis ofN-[(3R)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1-phenyl-1,2,4-triazole-3-carboxamide

1-Phenyl-1,2,4-triazole-3-carboxylic acid (1.2 g, 6.3 mmol),(3R)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-amine dihydrochloride (2.0g, 7.4 mmol), and diisopropylethylamine (13 mL, 75 mmol) were combinedtogether in 50 mL DMF. To this mixture was added HATU (2.5 g, 6.6 mmol).After stirring 3 minutes, LCMS of an aliquot indicated the reaction wascomplete. DIPEA and most of the DMF were removed under reduced pressure.The residue was diluted in 400 mL EtOAc and washed with 50 mL saturatedNaH₂PO₄. It was determined that a large amount of the desired productwas present in the organic phase, therefore it was extracted with 400 mL10 vol % i-PrOH/CHCl₃. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The crude product was purified by flashchromatography (SiO₂, 2-5% MeOH/dichloromethane) to provide 936 mg ofthe desired product (39% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H),7.74 (td, J=1.1, 7.5 Hz, 2H), 7.56-7.48 (m, 4H), 7.47-7.40 (m, 2H), 7.37(d, J=8.2 Hz, 1H), 7.33 (d, J=4.3 Hz, 1H), 5.00-4.80 (m, 1H), 4.50-4.35(br, 1H), 4.30-4.15 (br, 3H), 3.45-3.30 (m, 1H), 2.90-2.75 (m, 1H),2.50-2.38 (m, 1H), 2.25-2.15 (m, 1H). MS: (ES) 375.2 (M+H⁺).

Example 33: Synthesis ofN-[(3S)-1-(3-ethylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-1-phenyl-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

a) To a slurry of 2-(trichloroacetyl)pyrrole (380 mg, 1.79 mmol) andK₂CO₃ (780 mg, 5.7 mmol) in 5 mL acetone was added a solution of1-bromo-2-butanone (400 mg, 2.7 mmol) in 2 mL acetone. The mixture wasstirred for 19 hours at room temperature before filtering andconcentrating under reduced pressure to obtain3-ethyl-TH-pyrrolo[2,1-c][1,4]oxazin-1-one (298 mg, quantitative), whichwas used in the following step without purification.

b) To a 150 mL heavy wall glass pressure vessel were added the lactonefrom step a, 3-ethyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (2.6 g, 16mmol), NH₄OAc (6.0 g, 78 mmol), and acetic acid (40 mL). The vessel wassealed, immersed in a preheated oil bath set to 160° C., and stirred for3 hours. Afterward, acetic acid was removed under reduced pressure andthe residue was purified by flash chromatography (SiO₂, 2%MeOH/dichloromethane) to obtain 3-ethylpyrrolo[1,2-a]pyrazin-1(2H)-one(760 mg, 29% yield). MS: (ES) 163.1 (M+H⁺).

c) 3-Ethylpyrrolo[1,2-a]pyrazin-1(2H)-one from step b (760 mg, 4.7 mmol)was combined with POCl₃ (20 mL) and stirred at 80° C. for 20 minutes.POCl₃ was removed under reduced pressure. The residue was taken up inDCM and washed twice with saturated sodium bicarbonate. Afterward theorganic phase was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was used in thefollowing step without purification.

d) In a 20 mL vial were combined tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (610 mg, 3.3 mmol),1-chloro-3-ethylpyrrolo[1,2-a]pyrazine from step c (470 mg, 2.6 mmol),DIPEA (2.0 mmol, 11 mmol), and 1-butyl-3-methylimidazoliumtetrafluoroborate (100 mg, 0.4 mmol), and the mixture was heated for 45minutes at 110° C. 1-methylpyrrolidinone (1 mL) was added, followed byadditional tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (200 mg, 1.1mmol), and the reaction was stirred for an additional hour at 110° C. Anextra 400 mg (2.2 mmol) of the aminopyrroldine was then added, and themixture was stirred at 110° C. for an additional 20 minutes. Thereaction mixture was dried in vacuo and purified by flash chromatography(SiO₂, 2% 7 M NH₃ in MeOH/dichloromethane). The desired Boc-protectedintermediate was obtained after drying. The residue was taken up in aminimal amount of methanol and dichloromethane and treated with 4 M HClin dioxane (3 mL, 12 mmol). The mixture was heated at 50° C. and stirredfor 30 minutes, after which time the flask was removed from heat,allowed to cool to room temperature, and ether was added. The resultingbrown precipitate,(3S)-1-(3-ethylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride was collected by filtration and dried in vacuo; 638 mg,86% yield.

e) 1-Phenyl-1,2,4-triazole-3-carboxylic acid (34 mg 0.18 mmol),(3S)-1-(3-ethylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (63 mg, 0.21 mmol) and triethylamine (0.13 mL, 0.93mmol) were combined in 1 mL DMSO. HATU (74 mg, 0.19 mmol) was added andthe mixture was stirred for 40 minutes. DMSO was removed under reducedpressure and the residue was purified by reverse phase preparative HPLC(10-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the desired compound. ¹H NMR (400 MHz, CD₃OD) δ9.14 (s, 1H), 9.05 (d, J=6.7 Hz, 1H), 7.88 (d, J=7.4 Hz, 2H), 7.71 (s,1H), 7.60-7.46 (m, 5H), 6.89 (dd, J=2.8, 4.7 Hz, 1H), 4.95-4.80 (m, 1H),4.78-3.80 (br, 4H), 2.68 (q, J=7.4 Hz, 2H), 2.60-2.40 (m, 2H), 1.33 (t,J=7.4 Hz, 3H). MS: (ES) 402.2 (M+H⁺).

Example 34: Synthesis ofN-[(3S)-1-(3-ethylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-1-(4-fluorophenyl)-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

1-(4-fluorophenyl)-1,2,4-triazole-3-carboxylic acid (35 mg 0.17 mmol),(3s)-1-(3-ethylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (60 mg, 0.20 mmol) and triethylamine (0.12 mL, 0.86mmol) were combined in 1 mL DMSO. HATU (72 mg, 0.19 mmol) was added andthe mixture was stirred for 50 minutes. DMSO was removed under reducedpressure and the residue was purified by reverse phase preparative HPLC(10-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the desired compound. ¹H NMR (400 MHz, CD₃OD) δ9.10 (s, 1H), 7.92-7.88 (m, 2H), 7.71 (s, 1H), 7.53 (s, 2H), 7.35 (t,J=8.8 Hz, 2H), 6.89 (dd, J=2.4, 4.7 Hz, 1H), 4.95-4.80 (m, 1H),4.78-3.80 (br, 4H), 2.68 (q, J=7.4 Hz, 2H), 2.60-2.35 (m, 2H), 1.33 (t,J=7.4 Hz, 3H). MS: (ES) 420.2 (M+H⁺).

Example 35: Synthesis ofN-[(3S)-1-(3-ethylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-2-(4-hydroxy-1-piperidyl)thiazole-4-carboxamide.trifluoroacetatesalt

2-(4-Hydroxy-1-piperidyl)thiazole-4-carboxylic acid (40 mg 0.18 mmol),(3S)-1-(3-ethylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (60 mg, 0.20 mmol) and triethylamine (0.13 mL, 0.93mmol) were combined in 1 mL DMSO. HATU (77 mg, 0.20 mmol) was added andthe mixture was stirred for 40 minutes. DMSO was removed under reducedpressure and the residue was purified by reverse phase preparative HPLC(10-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the desired compound. ¹H NMR (400 MHz, CD₃OD) δ7.70 (d, J=2.4 Hz, 1H), 7.52-7.50 (m, 2H), 7.41 (s, 1H), 6.89 (dd,J=2.4, 4.3 Hz, 1H), 4.95-4.78 (m, 2H), 4.60-3.70 (br, 4H), 3.95-3.80 (m,2H), 3.36-3.20 (m, 2H), 2.68 (q, J=7.4 Hz, 2H), 2.60-2.30 (m, 2H),1.98-1.90 (m, 2H), 1.62-1.55 (m, 2H), 1.33 (t, J=7.4 Hz, 3H). MS: (ES)441.2 (M+H⁺).

Example 36:1-(4-fluorophenyl)-N-[(3R)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1,2,4-triazole-3-carboxamide

A mixture of 1-(4-fluorophenyl)-1,2,4-triazole-3-carboxylic acid (300 mg1.4 mmol), (3R)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-aminedihydrochloride (400 mg, 1.4 mmol) and triethylamine (1.5 mL, 11 mmol)were combined in 8 mL DMF. The mixture was stirred for 30 minutes beforeHATU (576 mg, 1.5 mmol) was added and the mixture was then stirred at60° C. for 1 hour. The mixture was chromatographed (SiO₂, 5-20%MeOH/EtOAc). A portion of the residue recovered from flashchromatography was purified by reverse phase preparative HPLC (10-30%gradient of CH₃CN/H₂O with 0.1% TFA modifier and concentrated underreduced pressure to give 70 mg of a TFA salt of the desired compound.The TFA salt was converted to the free base by suspending it insaturated NaCl (1 mL), adding 1 M NaOH (0.6 mL, 0.6 mmol), andextracting with dichloromethane. Removal of dichloromethane resulted ina glassy residue. The sample was dissolved in CH₃CN/H₂O and dried(lyophilizer) to obtain a white powder (28 mg, 5% yield). ¹H NMR (400MHz, DMSO) δ 9.31 (s, 1H), 8.92 (d, J=5.9 Hz, 1H), 7.92-7.85 (m, 3H),7.76 (s, 1H), 7.53 (s, 1H), 7.41 (t, J=9.0 Hz, 2H), 7.21 (d, J=4.7 Hz,1H), 4.65-4.50 (m, 1H), 4.48-3.65 (br, 4H), 2.30-2.05 (m, 2H). MS: (ES)393.2 (M+H⁺).

Example 37: Synthesis ofN-[(3S)-1-(3-isopropylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-1-phenyl-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

a) To a slurry of 2-(trichloroacetyl)pyrrole (5.3 g, 25 mmol) and K₂CO₃(11 g, 76 mmol) in 100 mL acetone was added a solution of1-bromo-3-methylbutan-2-one (4.5 g, 27 mmol) in 30 mL acetone. Themixture was stirred for 1 hour at 50° C. before filtering andconcentrating under reduced pressure to obtain3-isopropyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (4.1 g, 93%), which wasused in the following step without purification.

b) To a 150 mL heavy wall glass pressure tube were added the lactonefrom step a, 3-isopropyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (4.1 g, 23mmol), NH₄OAc (9.4 g, 122 mmol), and acetic acid (25 mL). The tube wassealed with a teflon bushing, immersed in a preheated oil bath set to160° C., and stirred for 9 hours at this temperature. The tube wasremoved from the bath, an additional 10 g (130 mmol) of NH₄OAc wasadded, and the reaction was stirred at 160° C. for an additional 3hours. Afterward, acetic acid was removed under reduced pressure, andthe residue was taken up in 150 mL DCM and 30 mL saturated NaHCO₃. Afterfiltration through celite, the aqueous phase was separated anddiscarded, the organic phase was concentrated and purified by flashchromatography (SiO₂, 1% MeOH/dichloromethane) to provide 2.0 grams of3-isopropylpyrrolo[1,2-a]pyrazin-1(2H)-one (49% yield). MS: (ES) 177.2(M+H⁺).

c) 3-isopropylpyrrolo[1,2-a]pyrazin-1(2H)-one from step b (1.6 g, 4.7mmol) was combined with POCl₃ (20 mL) and stirred at 70° C. for 20minutes. POCl₃ was removed under reduced pressure. The residue was takenup in DCM and washed twice with saturated sodium bicarbonate. Afterwardthe organic phase was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography (SiO₂, 5-10% MTBE/hexanes) to providechloro-3-isopropylpyrrolo[1,2-a]pyrazine (1.09 g, 62% yield).

d) In a 20 mL vial were combined tert-butylN-[(3S)-pyrrolidin-3-yl]carbamate (2.06 g, 11.1 mmol),1-chloro-3-isopropylpyrrolo[1,2-a]pyrazine from step c (1.09 g, 5.6mmol), DIPEA (4.0 mmol, 23 mmol), and 1-methylpyrrolidinone (1 mL) andthe mixture was heated with stirring in a vial at 110° C. for 1 hour.Temperature was decreased to 90° C. and the reaction was stirred foranother 16 hours. Afterward the organic reaction mixture was diluted inDCM (100 mL), washed with water (20 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography (SiO₂, 2% 7 M NH₃ in MeOH/dichloromethane). The desiredBoc-protected intermediate was obtained after drying. This was taken upin a minimal amount of methanol and dichloromethane and treated with 4 MHCl in dioxane (4 mL, 16 mmol). The mixture was heated at 50° C. andstirred for 20 minutes, after which time the flask was removed fromheat, allowed to cool to room temperature, and dioxane was added. Theresulting white precipitate,(3S)-1-(3-isopropylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride was collected by filtration and dried in vacuo; 925 mg,52% yield.

e) 1-phenyl-1,2,4-triazole-3-carboxylic acid (54 mg 0.29 mmol),(3S)-1-(3-isopropylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (98 mg, 0.31 mmol) and triethylamine (0.16 mL, 1.2 mmol)were combined in 0.6 mL DMSO. HATU (110 mg, 0.29 mmol) was added and themixture was stirred for 1 hour. DMSO was removed under reduced pressureand the residue was purified by reverse phase preparative HPLC (10-30%gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried (lyophilizer) togive the desired compound. ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 7.89(d, J=7.4 Hz, 2H), 7.73 (s, 1H), 7.60-7.46 (m, 5H), 6.90 (dd, J=2.7, 4.3Hz, 1H), 5.00-4.80 (m, 1H), 4.60-3.85 (br, 4H), 3.05-2.95 (m, 1H),2.60-2.38 (m, 2H), 1.35 (d, J=6.6 Hz, 6H). MS: (ES) 416.2 (M+H⁺).

Example 38: Synthesis of1-(4-fluorophenyl)-N-[(3S)-1-(3-isopropylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

1-(4-Fluorophenyl)-1,2,4-triazole-3-carboxylic acid (53 mg 0.26 mmol),(3S)-1-(3-isopropylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (91 mg, 0.29 mmol) and triethylamine (0.16 mL, 1.15mmol) were combined in 0.6 mL DMSO. HATU (104 mg, 0.27 mmol) was addedand the mixture was stirred for 1 hour. DMSO was removed under reducedpressure and the residue was purified by reverse phase preparative HPLC(10-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the desired compound. ¹H NMR (400 MHz, CD₃OD) δ9.10 (s, 1H), 7.92 (dd, J=4.7, 7.0 Hz, 2H), 7.73 (s, 1H), 7.57 (s, 1H),7.54 (d, J=4.3 Hz, 1H), 7.35 (t, J=8.6 Hz, 2H), 6.91 (dd, J=2.7, 4.3 Hz,1H), 5.00-4.85 (m, 1H), 4.60-3.65 (br, 4H), 3.05-2.95 (m, 1H), 2.60-2.38(m, 2H), 1.35 (d, J=7.0 Hz, 6H). MS: (ES) 434.2 (M+H⁺).

Example 39: Synthesis of2-(4-hydroxy-1-piperidyl)-N-[(3S)-1-(3-isopropylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]thiazole-4-carboxamide.trifluoroacetatesalt

2-(4-hydroxy-1-piperidyl)thiazole-4-carboxylic acid (54 mg, 0.24 mmol),(3S)-1-(3-isopropylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminedihydrochloride (81 mg, 0.26 mmol) and triethylamine (0.14 mL, 1.0 mmol)were combined in 0.6 mL DMSO. HATU (104 mg, 0.27 mmol) was added and themixture was stirred for 25 minutes. DMSO was removed under reducedpressure and the residue was purified by reverse phase preparative HPLC(10-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier) and dried(lyophilizer) to give the desired compound. ¹H NMR (400 MHz, CD₃OD) δ7.72 (d, J=2.4 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J=4.3 Hz, 1H), 7.41 (s,1H), 6.90-6.87 (m, 1H), 4.95-4.70 (m, 2H), 4.60-3.80 (br, 4H), 3.95-3.80(m, 2H), 3.36-3.20 (m, 2H), 3.05-2.95 (m, 1H), 2.60-2.30 (m, 2H),1.98-1.90 (m, 2H), 1.62-1.55 (m, 2H), 1.35 (d, J=6.6 Hz, 6H). MS: (ES)455.2 (M+H⁺).

Example 40: Synthesis of1-(2-fluorophenyl)-N-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

1-(2-Fluorophenyl)-1,2,4-triazole-3-carboxylic acid (41 mg 0.20 mmol),(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-amine dihydrochloride (69mg, 0.25 mmol), and triethylamine (0.11 mL, 0.80 mmol) were combined in0.5 mL DMSO. HATU (80 mg, 0.21 mmol) was added and the mixture wasstirred for 10 minutes. This was followed by the addition of acetic acid(0.1 mL), MeOH (0.4 mL) and water (1 mL), filtration, and purificationby reverse phase preparative HPLC (10-30% gradient of CH₃CN/H₂O with0.1% TFA modifier) and dried (lyophilizer) to give 40 mg of the thedesired compound (40% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.96 (d, J=2.7Hz, 1H), 8.05 (s, 1H), 7.95-7.82 (m, 3H), 7.56-7.38 (m, 3H), 7.17 (d,J=5.5 Hz, 1H), 5.00-3.65 (br, 5H), 2.60-2.38 (m, 2H). MS: (ES) 393.2(M+H⁺).

Example 41: Synthesis ofN-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1-(4-methylsulfonylphenyl)-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

a) A 100 mL flask was charged with methyl1H-1,2,4-triazole-3-carboxylate (2.8 g, 16 mmol), 4-iodopheynylboronicacid (4.0 g, 16 mmol), Cu(OAc)₂ (3.3 g, 18 mmol), pyridine (1.5 mL, 19mmol), and DMF (30 mL). The mixture was stirred on a preheated oil batheset to 90° C. for 30 minutes, during which time the solution changedcolor from a deep blue to a light green. The mixture was diluted inEtOAc (200 mL), filtered, and washed with 3:1 v/v saturated NH₄Cl-30%NH₄OH. The organic phase was concentrated in vacuo and the resultingresidue was purified by flash chromatography (SiO₂, 20%-60%EtOAc/hexanes) to obtain a white powder of methyl1-(4-iodophenyl)-1,2,4-triazole-3-carboxylate (830 mg, 16% yield).

b) Methyl 1-(4-iodophenyl)-1,2,4-triazole-3-carboxylate (830 mg, 2.5mmol) was dissolved in MeOH (20 mL) and THF (10 mL). 1 M NaOH (2.5 mL,2.5 mmol) was added and the mixture stirred at room temperature for 2 h.Additional 1 M NaOH was added (2.5 mL, 2.5 mmol) and the reaction washeated to 50° C. for 30 minutes. After cooling to room temperature, thepH was adjusted to 4 by the addition of 6 M HCl, MeOH and THF wereremoved under reduced pressure and the resulting white precipitate wascollected by filtration and dried in vacuo to obtain 680 mg (86% yield)of 1-(4-iodophenyl)-1,2,4-triazole-3-carboxylic acid.

c) To a suspension of 1-(4-iodophenyl)-1,2,4-triazole-3-carboxylic acid(680 mg, 2.15 mmol) in 1,2-dichloroethane (8 mL) was added oxalylchloride (0.30 mL, 3.4 mmol), followed by DMF (0.020 mL, 0.26 mmol). Themixture was stirred in a 50° C. oil bath for 5 minutes, and afterwardwas concentrated under reduced pressure and dried in vacuo. The residueobtained was suspended in DCM (10 mL) and to this was added(3S)-1-imidazo-[1,2-a]pyrazin-8-ylpyrrolidin-3-amine dihydrochloride(650 mg, 2.36 mmol), followed by DIPEA (1.5 mL, 8.6 mmol). The mixturewas stirred, briefly brought to a boil, removed from the heat source andstirred for an additional 20 minutes. After concentrating under reducedpressure, the residue was purified by flash chromatography (SiO₂; 2%MeOH/dichloromethane) to obtain 886 mg of a white foam (82% yield).

d)N-[(3S)-1-Imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1-(4-iodophenyl)-1,2,4-triazole-3-carboxamidefrom step c (73 mg, 0.15 mmol), sodium methanesulfinate (31 mg, 0.30mmol), CuI (5.4 mg, 0.028 mmol), proline (6.8 mg, 0.059 mmol), Cs₂CO₃(23 mg, 0.70 mmol) and DMSO (0.40 mL) were combined together in a 4 mLvial and stirred at 120° C. for 3 h. The reaction mixture was purifiedby reverse phase preparative HPLC (10-30% gradient of CH₃CN/H₂O with0.1% TFA modifier) and dried (lyophilizer) to give the desired compound.¹H NMR (400 MHz, CD3OD) d 9.31 (s, 1H), 9.15 (d, J=7.0 Hz, 0.5H),8.20-8.10 (m, 4H), 8.05 (s, 1H), 7.95 (d, J=5.4 Hz, 1H), 7.82 (s, 1H),7.18 (d, J=5.8 Hz, 1H), 5.00-3.65 (br, 5H), 3.18 (s, 3H), 2.60-2.38 (m,2H). MS: (ES) 453.2 (M+H⁺).

Example 42: Synthesis ofN-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1-(p-tolyl)-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

In a 4 mL vial were combinedN-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1-(4-iodophenyl)-1,2,4-triazole-3-carboxamide(64 mg, 0.13 mmol), methylboronic acid (32 mg, 0.53 mmol),(1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (9.5 mg,0.013 mmol), CsF (67 mg, 0.44 mmol), and degassed dioxane (0.80 mL). Thevial was sealed and stirred at 90° C. for 2 hours. Dioxane was removedunder reduced pressure and the residue was purified by reverse phasepreparative HPLC (10-30% gradient of CH₃CN/H₂O with 0.1% TFA modifier)and dried (lyophilizer) to give the desired compound. ¹H NMR (400 MHz,CD₃OD) δ 9.07 (s, 1H), 8.05 (s, 1H), 7.94 (d, J=5.9 Hz, 1H), 7.82 (s,1H), 7.74 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.17 (d, J=5.4 Hz,1H), 5.00-3.65 (br, 5H), 2.60-2.38 (m, 2H), 2.41 (s, 1H). MS: (ES) 389.2(M+H⁺).

Example 43: Synthesis of1-(4-fluorophenyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]-1,2,4-triazole-3-carboxamide.trifluoroacetatesalt

To a suspension of 1-(4-fluorophenyl)-1,2,4-triazole-3-carbonyl chloride(70 mg, 0.31 mmol) in DCM (10 mL) was added(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-amine dihydrochloride (104mg, 0.38 mmol), followed by DIPEA (0.70 mL, 4.0 mmol). The reactionmixture was stirred 10 minutes, concentrated under reduced pressure, andpurified by reverse phase preparative HPLC (10-30% gradient of CH₃CN/H₂Owith 0.1% TFA modifier) and dried (lyophilizer) to give the desiredcompound. ¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 7.91-7.88 (m, 2H),7.79 (dd, J=1.2, 2.8 Hz, 1H), 7.74 (d, J=5.9 Hz, 1H), 7.59 (d, J=4.3 Hz,1H), 7.34 (t, J=8.6 Hz, 2H), 6.95 (dd, J=2.8, 4.7 Hz, 1H), 6.86 (d,J=5.5 Hz, 1H), 5.00-4.85 (m, 1H), 4.80-3.65 (br, 4H), 2.60-2.38 (m, 2H).MS: (ES) 392.2 (M+H⁺).

Example 44: Synthesis of1-(4-cyanophenyl)-N-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1,2,4-triazole-3-carboxamide

To a 4 mL vial were addedN-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-1-(4-iodophenyl)-1,2,4-triazole-3-carboxamide(82 mg, 0.16 mmol), Zn(CN)₂ (24 mg, 0.20 mmol),tetrakis(triphenylphospine)palladium(0) (23 mg, 0.020 mmol), anddegassed DMF. The vial was sealed and the mixture stirred at 80° C. for1 hour. DMF was removed under reduced pressure and the residue waspurified by flash chromatography (SiO₂, 7 M NH₃ in MeOH/dichloromethane)to obtain 48 mg of white powder of the desired product (74% yield). ¹HNMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 7.94 (d, J=6.6 Hz, 2H), 7.85 (d,J=6.6 Hz, 2H), 7.55 (s, 1H), 7.50 (s, 1H), 7.44 (d, J=4.3 Hz, 1H),7.40-7.30 (m, 2H), 5.00-4.85 (m, 1H), 4.50-4.35 (br, 1H), 4.30-4.15 (br,3H), 2.50-2.38 (m, 1H), 2.25-2.15 (m, 1H). MS: (ES) 400.1 (M+H⁺).

Example 45: Synthesis of1-(4-chlorophenyl)-N-[(3S)-3-(hydroxymethyl)-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl]pyrazole-3-carboxamide

a) To a mixture of 1 (1.0 g, 4.6 mmol) and 580 mg of 2 (580 mg, 3.8mmol) was added 1.7 ml of Hunig's base (9.5 mmol). The resulting mixturewas stirred at 130° C. for 3 h. After the mixture was cooled down toroom temperature, 200 ml of isopropanol/chloroform (1:2) was added, andthe organics were washed with saturated aqueous NaHCO₃ (2×20 ml) andbrine (2×50 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via flash columnchromatography on silica gel (0-10% MeOH in EtOAc) to get the desiredproduct 3 as a brown powder (700 mg, 46%).

b) A mixture of 3 (332 mg, 1.0 mmol) and 3 mL of 4.0 M of HCl in dioxane(12 mmol) was stirred at 50° C. for 1 h. Then the mixture wasconcentrated under reduced pressure to give a brown powder (300 mg,98%), which was used for next step without further purification.

c) A 10 mL vial was charged with intermediate A2 (92 mg, 0.417 mmol),intermediate B1 (122 mg, 0.40 mmol), HATU (166 mg, 0.437 mmol), Hunig'sbase (146 mg, 1.12 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and was then diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preparative HPLC toget the desired product (105 mg, 60%). ¹H NMR (400 MHz, CD₃OD) δ 8.28(d, J=2.5 Hz, 1H), 7.85 (dd, J=2.2, 6.9 Hz, 2H), 7.48 (dd, J=2.2, 6.9Hz, 2H), 7.42 (d, J=5.2 Hz, 1H), 7.39 (dd, J=1.1, 2.6 Hz, 1H), 6.98 (d,J=4.4 Hz, 1H), 6.93 (d, J=2.6 Hz, 1H), 6.86 (d, J=5.1 Hz, 1H), 6.65 (dd,J=2.5, 4.1 Hz, 1H), 4.34 (d, J=11.4 Hz, 1H), 4.15 (d, J=11.4 Hz, 1H),4.02-3.88 (m, 4H), 2.65-2.55 (m, 1H), 2.45-2.36 (m, 1H); MS: (ES) m/zcalculated for C₂₂H₂₁ClN₆O₂ [M+H]⁺ 437.2, found 437.

Example 46: Synthesis of1-(4-fluorophenyl)-N-[(3S)-3-(hydroxymethyl)-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl]pyrazole-3-carboxamide

To a 10 mL vial was charged with intermediated A3 (83 mg, 0.417 mmol),intermediate B1 (122 mg, 0.40 mmol), HATU (166 mg, 0.437 mmol), Hunig'sbase (146 mg, 1.12 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics was dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via HPLC to get thedesired product (120 mg, 71%). ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J=2.6Hz, 1H), 7.86-7.82 (m, 2H), 7.42 (d, J=4.7 Hz, 1H), 7.38 (t, J=1.5 Hz,1H), 7.21 (dt, J=2.2, 8.4 Hz, 2H), 6.98 (d, J=4.4 Hz, 1H), 6.91 (d,J=2.5 Hz, 1H), 6.86 (d, J=4.7 Hz, 1H), 6.64 (dd, J=2.5, 4.0 Hz, 1H),4.34 (d, J=11.4 Hz, 1H), 4.15 (d, J=11.4 Hz, 1H), 4.02-3.88 (m, 4H),2.65-2.55 (m, 1H), 2.45-2.36 (m, 1H); MS: (ES) m/z calculated forC₂₂H₂₁FN₆O₂[M+H]⁺ 421.2, found 421.

Example 47: Synthesis ofN-[(3S)-3-(hydroxymethyl)-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl]-2-(4-hydroxy-1-piperidyl)thiazole-4-carboxamide

A 10 mL vial was charged with intermediated A4 (90 mg, 0.395 mmol),intermediate B1 (122 mg, 0.40 mmol), HATU (166 mg, 0.437 mmol), Hunig'sbase (146 mg, 1.12 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via HPLC to get thedesired product (85 mg, 49%). ¹H NMR (400 MHz, CD₃OD) δ 8.07 (s, 1H),7.80-7.76 (m, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.56 (d, J=4.4 Hz, 1H), 7.37(s, 1H), 6.94 (dd, J=2.4, 4.4 Hz, 1H), 6.85 (d, J=6.0 Hz, 1H), 4.80-4.60(br, 1H), 4.50-4.20 (br, 2H), 4.02-3.80 (m, 4H), 3.35-3.25 (m, 4H),2.78-2.66 (m, 1H), 2.56-2.45 (m, 1H), 1.98-1.88 (m, 2H), 1.64-1.52 (m,2H); MS: (ES) m/z calculated for C₂₁H₂₆N₆O₃S [M+H]⁺ 443.2, found 443.

Example 48: Synthesis ofN-[(3S)-3-(hydroxymethyl)-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl]-1-phenyl-1,2,4-triazole-3-carboxamide

A 10 mL vial was charged with intermediated A5 (76 mg, 0.40 mmol),intermediate B1 (122 mg, 0.40 mmol), HATU (166 mg, 0.437 mmol), Hunig'sbase (146 mg, 1.12 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preparative HPLC toget the desired product (110 mg, 62%). ¹H NMR (400 MHz, CD₃OD) δ 9.12(s, 1H), 7.85 (td, J=1.5, 7.4 Hz, 2H), 7.76 (d, J=2.2 Hz, 1H), 7.70 (d,J=5.5 Hz, 2H), 7.55 (m, 2H), 7.46 (m, 1H), 6.92 (s, 1H), 6.83 (d, J=5.5Hz, 1H), 4.60-3.80 (br, 4H), 4.02 (s, 2H), 2.82-2.70 (m, 1H), 2.58-2.48(m, 1H); MS: (ES) m/z calculated for C₂₁H₂₁N₇O₂ [M+H]⁺ 404.2, found 404.

Example 49: Synthesis of1-(4-fluorophenyl)-N-[(3S)-3-(hydroxymethyl)-1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl]pyrazole-3-carboxamide

a) To a mixture of 1 (1.0 g, 4.6 mmol) and 580 mg of 2 (580 mg, 3.8mmol) was added 1.7 ml of Hunig's base (9.5 mmol). The resulting mixturewas stirred at 130° C. for 3 h. After the mixture was cooled down toroom temperature 200 ml of isopropanol/chloroform (1:2) was added, andthe organics were washed with saturated aqueous NaHCO₃ (2×20 ml) andbrine (2×50 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified through flash columnchromatography on silica gel (0-10% MeOH in EtOAc) to get the desiredproduct 3 as a brown powder (900 mg, 58%).

b) A mixture of 3 (333 mg, 1 mmol) and 3 mL of 4.0 M HCl in dioxane (12mmol) was stirred at 50° C. for 1 h. Then the mixture was concentratedunder reduced pressure to give a brown powder (300 mg, 98%), which wasused for next step without further purification.

c) A 10 mL vial was charged with intermediated A3 (86 mg, 0.417 mmol),intermediate B2 (120 mg, 0.40 mmol), HATU (166 mg, 0.437 mmol), Hunig'sbase (146 mg, 1.12 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via HPLC to get thedesired product (118 mg, 71%). ¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J=2.5Hz, 1H), 8.01 (d, J=1.1 Hz, 1H), 7.89 (d, J=5.7 Hz, 1H), 7.86-7.82 (m,2H), 7.78 (s, 1H), 7.22 (t, J=8.8 Hz, 2H), 7.12 (d, J=5.5 Hz, 1H), 6.91(d, J=2.6 Hz, 1H), 4.60-3.80 (br, 4H), 4.00 (s, 2H), 2.80-2.70 (m, 1H),2.56-2.46 (m, 1H); MS: (ES) m/z calculated for C₂₁H₂₀FN₇O₂[M+H]⁺ 422.2,found 422.

Example 50: Synthesis ofN-[(3S)-3-(hydroxymethyl)-1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl]-2-(4-hydroxy-1-piperidyl)thiazole-4-carboxamide

A 10 mL vial was charged with intermediated A4 (90 mg, 0.395 mmol),intermediate B2 (120 mg, 0.40 mmol), HATU (166 mg, 0.437 mmol), Hunig'sbase (146 mg, 1.12 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (81 mg, 49%). ¹H NMR (400 MHz, CD₃OD) δ 8.02 (s,1H), 7.90 (d, J=5.5 Hz, 1H), 7.79 (s, 1H), 7.35 (s, 2H), 7.14 (d, J=5.8Hz, 1H), 4.60-3.80 (br, 4H), 3.94 (s, 2H), 3.90-3.80 (m, 3H), 3.32-3.20(m, 2H), 2.75-2.65 (m, 1H), 2.52-2.45 (m, 1H), 1.97-1.87 (m, 2H),1.64-1.50 (m, 2H); MS: (ES) m/z calculated for C₂₀H₂₅N₇O₃S [M+H]⁺ 444.2,found 444.

Example 51: Synthesis ofN-[(3S)-3-(hydroxymethyl)-1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl]-1-phenyl-1,2,4-triazole-3-carboxamide

A 10 mL vial was charged with intermediated A5 (76 mg, 0.40 mmol),intermediate B2 (122 mg, 0.40 mmol), HATU (166 mg, 0.437 mmol), Hunig'sbase (146 mg, 1.12 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified vie preperative HPLC toget the desired product (110 mg, 62%). ¹H NMR (400 MHz, CD₃OD) δ 9.12(s, 1H), 8.02 (d, J=1.1 Hz, 1H), 7.90 (d, J=5.9 Hz, 1H), 7.84 (dd,J=1.5, 8.8 Hz, 2H), 7.79 (s, 1H), 7.55 (t, J=7.3 Hz, 2H), 7.46 (t, J=7.3Hz, 1H), 7.13 (d, J=5.5 Hz, 1H), 4.02 (s, 2H), 4.60-3.80 (br, 4H),2.80-2.70 (m, 1H), 2.58-2.48 (m, 1H); MS: (ES) m/z calculated forC₂₀H₂₀N₈O₂ [M+H]⁺ 405.2, found 405.

Example 52: Synthesis of1-(4-fluorophenyl)-N-[(3R,4S)-4-hydroxy-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl]pyrazole-3-carboxamide

a) To a mixture of t (120 mg, 0.59 mmol) and 2 (90 mg, 0.59 mmol) wasadded 1.0 ml of Hunig's base (5.5 mmol). The resulting mixture wasstirred at 130° C. for 3 h. After the mixture was cooled down to roomtemperature, 200 ml of isopropanol/chloroform (1:2) was added, and theorganics were washed with saturated aqueous NaHCO₃ (2×20 ml) and brine(2×50 ml). The organics were dried over MgSO₄ and concentrated underreduced pressure. The residue was purified via flash columnchromatography on silica gel (0-10% MeOH in EtOAc) to get the desiredproduct 3 as a brown powder (150 mg, 79%).

b) A mixture of 3 (150 mg, 0.47 mmol) and 2 mL of 4.0 M HCl in dioxane(8.0 mmol) was stirred at 50° C. for 1 h. Then the mixture wasconcentrated under reduced pressure to give a brown powder (130 mg,95%), which was used for the next step without further purification.

c) A 10 mL vial was charged with intermediated A3 (43 mg, 0.209 mmol),intermediate B2 (60 mg, 0.20 mmol), HATU (83 mg, 0.218 mmol), Hunig'sbase (73 mg, 0.56 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (54 mg, 50%). ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d,J=2.6 Hz, 1H), 7.89-7.84 (m, 2H), 7.77 (d, J=1.5 Hz, 1H), 7.72 (d, J=5.9Hz, 1H), 7.57 (d, J=4.4 Hz, 1H), 7.26 (t, J=8.8 Hz, 2H), 6.98 (d, J=2.2Hz, 1H), 6.92 (t, J=3.0 Hz, 1H), 6.84 (d, J=5.8 Hz, 1H), 4.85 (m, 1H),4.64 (m, 1H), 4.70-3.60 (br, 4H); MS: (ES) m/z calculated forC₂₁H₁₉FN₆O₂[M+H]⁺ 407.2, found 407.

Example 53: Synthesis of intermediate A1

a) A 50 mL flask was charged with 1.89 g of starting material 1 (15mmol), 1.96 g of starting material 2 (10 mmol), 400 mg of CuI (2.0mmol), 4.5 g of K₂CO₃ (3.3 mmol) and 0.9 mL oftrans-N,N′-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixturewas stirred at 140° C. for 3 h. After the mixture was cooled down toroom temperature, 200 mL of EtOAc was added and the organics were washedwith water (2×50 mL), brine (2×50 mL). The organics were dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedvia flash chromatography on silica gel (0-25% EtOAc in hexanes) to getthe desired product 3 (1.2 g, 50%).

b) To a solution of the ester 3 (240 mg, 1 mmol) in THF was added 3.0 mLof 1.0 M LiOH (3.0 mmol). The resulting mixture was stirred at roomtemperature for 3 h. 1.0 M HCl was added to adjust the pH to 1.0 and theorganics were extracted with EtOAc (2×100 mL), followed by drying overMgSO₄. Concentration under reduced pressure gave the product as a whitesolid (217 mg, 96%), which was used for the next step without furtherpurification.

Example 54: Synthesis of1-[2-(cyanomethyl)phenyl]-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamide

A 10 mL vial was charged with intermediate A1 (45 mg, 0.20 mmol),intermediate B4 (55 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), Hunig'sbase (73 mg, 0.6 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and was then diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (56 mg, 68%). ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d,J=2.2 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J=5.5 Hz, 1H), 7.60-7.48 (m, 5H),6.98 (d, J=2.5 Hz, 1H), 6.91 (dd, J=2.6, 4.4 Hz, 1H), 6.82 (d, J=5.8 Hz,1H), 4.95-3.65 (br, 5H), 3.93 (s, 2H), 2.55-2.30 (m, 2H); MS: (ES) m/zcalculated for C₂₃H₂₁N₇O [M+H]⁺ 412.2, found 412.

Example 55: Synthesis of1-[2-(cyanomethyl)phenyl]-N-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]pyrazole-3-carboxamide

A 10 mL vial was charged with intermediated A1 (45 mg, 0.20 mmol),intermediate B5 (58 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), Hunig'sbase (78 mg, 0.6 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (60 mg, 56%). ¹H NMR (400 MHz, CD₃OD) δ 8.02 (d,J=2.2 Hz, 1H), 7.65-7.57 (m, 3H), 7.54-7.46 (m, 3H), 6.97 (d, J=2.2 Hz,1H), 6.75-6.72 (m, 2H), 4.82-4.75 (m, 1H), 4.28-4.24 (m, 1H), 4.08-4.00(m, 1H), 3.98-3.90 (m, 4H), 2.61 (s, 3H), 2.52-2.30 (m, 2H); MS: (ES)m/z calculated for C₂₄H₂₃N₇O [M+H]⁺ 426.2, found 426.

Example 56: Synthesis of1-(4-chloro-3-fluoro-phenyl)-N-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]pyrazole-3-carboxamideand1-(3-fluorophenyl)-N-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]pyrazole-3-carboxamide

A 10 mL vial was charged with intermediate A6 (48 mg, 0.20 mmol),intermediate B5 (58 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), Hunig'sbase (78 mg, 0.6 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the chlorofluoro (40 mg, 46%) and a fluoro (5 mg, 6%) products.1-(4-chloro-3-fluoro-phenyl)-N-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]pyrazole-3-carboxamide:¹H NMR (400 MHz, CD₃OD) δ 8.36 (d, J=2.6 Hz, 1H), 7.90 (dd, J=2.6, 10.3Hz, 1H), 7.72-7.64 (m, 3H), 7.61 (t, J=8.0 Hz, 1H), 6.95 (d, J=2.6 Hz,1H), 6.77-6.73 (m, 2H), 4.82-4.75 (m, 1H), 4.30-4.24 (m, 1H), 4.08-3.92(m, 3H), 2.63 (s, 3H), 2.52-2.30 (m, 2H); MS: (ES) m/z calculated forC₂₂H₂₀ClFN₆O [M+H]⁺ 439.2, found 439.1-(3-fluorophenyl)-N-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]pyrazole-3-carboxamide:¹H NMR (400 MHz, CD₃OD) δ 8.35 (d, J=2.6 Hz, 1H), 7.76-7.64 (m, 3H),7.53 (dt, J=6.2, 8.4 Hz, 2H), 7.13 (dt, J=2.5, 8.4 Hz, 1H), 6.95 (d,J=2.6 Hz, 1H), 6.77-6.73 (m, 2H), 4.82-4.75 (m, 1H), 4.30-4.24 (m, 1H),4.08-3.92 (m, 3H), 2.63 (s, 3H), 2.52-2.30 (m, 2H); MS: (ES) m/zcalculated for C₂₂H₂₁FN₆O [M+H]⁺ 405.2, found 405.

Example 57: Synthesis of2-(4-hydroxy-1-piperidyl)-N-[(3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]thiazole-4-carboxamide

A 10 mL vial was charged with intermediated A4 (45 mg, 0.20 mmol),intermediate B5 (58 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), Hunig'sbase (78 mg, 0.6 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (35 mg, 41%). ¹H NMR (400 MHz, CD₃OD) δ7.68-7.65 (m, 2H), 7.38 (s, 1H), 6.76-6.74 (m, 2H), 4.75-4.65 (m, 1H),4.25-4.15 (m, 1H), 4.06-3.80 (m, 5H), 3.35-3.20 (m, 3H), 2.62 (s, 1H),2.50-2.30 (m, 2H), 1.98-1.90 (m, 2H), 1.65-1.52 (m, 2H); MS: (ES) m/zcalculated for C₂₁H₂₆N₆O₂S [M+H]⁺ 427.2, found 427.

Example 58: Synthesis of1-(4-chloro-3-fluoro-phenyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamideand1-(3-fluorophenyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamide

A 10 mL vial was charged with intermediated A6 (48 mg, 0.20 mmol),intermediate B6 (58 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), Hunig'sbase (78 mg, 0.6 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the 4-chloro-3-fluoro product (38 mg, 45%) and and the 3-fluoroproduct (8 mg, 10%). Synthesis of1-(4-chloro-3-fluoro-phenyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamide:¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J=2.9 Hz, 1H), 7.91 (dd, J=2.6, 10.3Hz, 1H), 7.77 (s, 1H), 7.71-7.68 (m, 2H), 7.61-7.55 (m, 2H), 6.97 (d,J=2.6 Hz, 1H), 6.92 (dd, J=2.6, 4.4 Hz, 1H), 6.84 (d, J=5.9 Hz, 1H),4.95-3.70 (br, 5H), 2.60-2.36 (m, 2H); MS: (ES) m/z calculated forC₂₁H₁₈ClFN₆O [M+H]⁺ 425.2, found 425.1-(3-fluorophenyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamide:¹H NMR (400 MHz, CD₃OD) δ 8.80 (d, J=5.9 Hz, 1H), 8.38 (d, J=2.3 Hz,1H), 7.79-7.68 (m, 4H), 7.59-7.48 (m, 2H), 7.14 (dt, J=2.8, 8.6 Hz, 1H),6.98 (d, J=2.4 Hz, 1H), 6.95 (dd, J=2.6, 4.4 Hz, 1H), 6.86 (d, J=5.5 Hz,1H), 4.95-3.70 (br, 5H), 2.60-2.36 (m, 2H); MS: (ES) m/z calculated forC₂₁H₁₉FN₆O [M+H]⁺ 391.2, found 391.

Example 59: Synthesis of2-(4-hydroxy-1-piperidyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]thiazole-4-carboxamide

A 10 mL vial was charged with intermediate A4 (45 mg, 0.20 mmol),intermediate B6 (55 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), Hunig'sbase (78 mg, 0.6 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (65 mg, 79%). ¹H NMR (400 MHz, CD₃OD) δ 7.76 (s,1H), 7.70 (d, J=5.8 Hz, 1H), 7.54 (d, J=3.7 Hz, 1H), 7.39 (s, 1H), 7.53(dd, J=2.5, 4.0 Hz, 1H), 6.84 (d, J=5.5 Hz, 1H), 4.82-4.75 (m, 1H),4.70-3.60 (br, 4H), 3.90-3.80 (m, 2H), 3.40-3.20 (m, 3H), 2.52-2.30 (m,2H), 1.96-1.90 (m, 2H), 1.65-1.52 (m, 2H); MS: (ES) m/z calculated forC₂₀H₂₄FN₆O₂S [M+H]⁺ 413.2, found 413.

Example 60: Synthesis of1-(5-chloro-2-pyridyl)-N-[(3S)-1-pyrrolo[1,2-a]pyrazin-1-ylpyrrolidin-3-yl]pyrazole-3-carboxamide

A 10 mL vial was charged with intermediated A7 (45 mg, 0.20 mmol),intermediate B6 (55 mg, 0.20 mmol), HATU (83 mg, 0.22 mmol), Hunig'sbase (78 mg, 0.6 mmol) and 2 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (45 mg, 56%). ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s,1H), 8.44 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.77(s, 1H), 7.72 (d, J=5.9 Hz, 1H), 7.57 (d, J=4.4 Hz, 1H), 6.96 (s, 1H),6.94-6.91 (m, 1H), 6.85 (d, J=5.9 Hz, 1H), 5.00-3.65 (br, 5H), 2.60-2.30(m, 2H); MS: (ES) m/z calculated for C₂₀H₁₈ClN₇O [M+H]⁺ 408.2, found408.

Example 61: Synthesis of2-(4-hydroxy-1-piperidyl)-N-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]thiazole-4-carboxamide

A 10 mL vial was charged with intermediated A4 (90 mg, 0.40 mmol),intermediate B7 (100 mg, 0.40 mmol), HATU (166 mg, 0.40 mmol), Hunig'sbase (156 mg, 1.2 mmol) and 4 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (80 mg, 48%). ¹H NMR (400 MHz, CD₃OD) δ 7.74 (s,1H), 7.66 (d, J=4.7 Hz, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.22 (d, J=4.9Hz, 1H), 4.76-4.65 (m, 1H), 4.40-4.30 (m, 1H), 4.20-3.75 (m, 4H),3.40-3.20 (m, 4H), 2.42-2.10 (m, 2H), 1.95-1.85 (m, 2H), 1.65-1.50 (m,2H); MS: (ES) m/z calculated for C₁₉H₂₃N₇O₂S [M+H]⁺ 414.2, found 414.

Example 62: Synthesis of1-(4-fluorophenyl)-N-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]-5-methyl-1,2,4-triazole-3-carboxamide

A 10 mL vial was charged with intermediated A8 (82 mg, 0.30 mmol),intermediate B7 (82 mg, 0.30 mmol), HATU (125 mg, 0.33 mmol), Hunig'sbase (160 mg, 1.23 mmol) and 4 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (65 mg, 53%). ¹H NMR (400 MHz, CD₃OD) δ 8.95 (d,J=6.3 Hz, 0.2H), 8.05 (s, 1H), 7.94 (d, J=5.5 Hz, 1H), 7.81 (s, 1H),7.64-7.59 (m, 2H), 7.36-7.30 (m, 2H), 7.17 (d, J=5.4 Hz, 1H), 5.00-4.85(m, 1H), 4.80-3.65 (br, 4H), 2.51 (s, 3H), 2.60-2.38 (m, 2H); MS: (ES)m/z calculated for C₂₀H₁₉FN₈O [M+H]⁺ 407.2, found 407.

Example 63: Synthesis of2-(4-hydroxy-1-piperidyl)-N-[(3S)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]thiazole-4-carboxamide

A 10 mL vial was charged with intermediated A4 (90 mg, 0.40 mmol),intermediate B8 (100 mg, 0.40 mmol), HATU (166 mg, 0.40 mmol), Hunig'sbase (156 mg, 1.2 mmol) and 4 mL of DMF. The mixture was stirred at roomtemperature for 1 h and then was diluted with 100 ml ofisopropanol/chloroform (1:2), followed by washing with water (2×20 ml)and brine (2×20 ml). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via preperative HPLC toget the desired product (75 mg, 45%). ¹H NMR (400 MHz, CD₃OD) δ 9.06 (s,1H), 7.64 (d, J=4.8 Hz, 1H), 7.36 (s, 1H), 7.26 (d, J=4.8 Hz, 1H),4.73-4.68 (m, 1H), 4.60-3.60 (br, 4H), 3.96-3.80 (m, 3H), 3.35-3.20 (m,2H), 2.45-2.35 (m, 1H), 2.30-2.18 (m, 1H), 1.95-1.88 (m, 2H), 1.62-1.50(m, 2H); MS: (ES) m/z calculated for C₁₈H₂₂N₈O₂S [M+H]⁺ 415.2, found415.

Example 64: Synthesis of3-[[1-(4-fluorophenyl)pyrazole-3-carbonyl]amino]-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidine-3-carboxylicacid andN-3-carbamoyl-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl-1-(4-fluorophenyl)pyrazole-3-carboxamide

a) To a mixture of a (248 mg, 1.0 mmol) and b (152 mg, 1.0 mmol) wasadded 2.0 mL of Hunig's base (9.5 mmol). The resulting mixture wasstirred at 130° C. for 3 h. After the mixture was cooled down to roomtemperature, 100 mL of isopropanol/chloroform (1:2) was added, and themixture was then washed with saturated aqueous NaHCO₃ (2×20 mL) andbrine (2×50 mL). The organics were dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified via flashchromatography on silica gel (0-10% MeOH in EtOAc) to get the desiredproduct c as a brown powder (250 mg, 67%).

b) A mixture of c (250 mg, 0.67 mmol) and 2 mL of 4.0 M HCl in dioxane(8 mmol) was stirred at 50° C. for 1 h. The mixture was thenconcentrated under reduced pressure to give a brown powder (228 mg,98%), which was used as intermediate B9 for next step without furtherpurification.

c) A 10 mL vial was charged with intermediated A3 (136 mg, 0.66 mmol),intermediate B9 (228 mg, 0.66 mmol), HATU (274 mg, 0.72 mmol), Hunig'sbase (257 mg, 1.98 mmol) and 5 mL of DMF. The mixture was stirred atroom temperature for 1 h and then was diluted with 100 ml of EtOAc,followed by washing with water (2×20 ml) and brine (2×20 ml). Theorganics were dried over MgSO₄ and concentrated under reduced pressure.The residue was purified via flash chromatograhy on sica gel (50-100%EtOAc in hexanes) to get the desired product d (220 mg, 72%).

d) A 10 mL vial was charged with d (230 mg, 0.50 mmol), 1 N LiOH (3 ml)and 3 mL of MeOH. The mixture was stirred at room temperature for 1 hand then was adjusted to pH 3.0. The mixture was then extracted with 100mL of EtOAc, followed by washing with water (2×20 mL) and brine (2×20mL). The organics were dried over MgSO₄ and concentrated under reducedpressure. The residue was purified via flash column chromatograhy onsica gel (100% EtOAc in hexanes) to get the desired product (205 mg,95%).3-[[1-(4-fluorophenyl)pyrazole-3-carbonyl]amino]-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidine-3-carboxylicacid: ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J=2.7 Hz, 1H), 7.89 (m, 2H),7.78 (dd, J=1.2, 2.7 Hz, 1H), 7.73 (d, J=5.4 Hz, 1H), 7.55 (d, J=3.5 Hz,1H), 7.30-7.22 (m, 2H), 6.97 (d, J=2.7 Hz, 1H), 6.94 (dd, J=2.8, 4.3 Hz,1H), 6.84 (d, J=5.5 Hz, 1H), 4.60-3.80 (br, 4H), 2.90-2.82 (m, 1H),2.80-2.70 (m, 1H); MS: (ES) m/z calculated for C₂₂H₁₉FN₆O₃[M+H]⁺ 435.2,found 435.

e) A 10 mL vial was charged3-[[1-(4-fluorophenyl)pyrazole-3-carbonyl]amino]-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidine-3-carboxylicacid (100 mg, 0.25 mmol), HATU (114 mg, 0.3 mmol), saturated NH₃ in DCM(2 mL) and 5 mL of DMF. The mixture was stirred at room temperature for1 h and then was diluted with 100 ml of EtOAc, followed by washing withwater (2×20 mL) and brine (2×20 mL). The organics were dried over MgSO₄and concentrated under reduced pressure. The residue was purified viaflash chromatograhy on sica gel (50-100% EtOAc in hexanes) to get thedesired product (75 mg, 69%).N-3-carbamoyl-1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl-1-(4-fluorophenyl)pyrazole-3-carboxamide:¹H NMR (400 MHz, CD₃OD) δ 8.30 (d, J=2.4 Hz, 1H), 7.88 (m, 2H), 7.78 (q,J=1.2 Hz, 1H), 7.72 (d, J=5.9 Hz, 1H), 7.55 (d, J=3.9 Hz, 1H), 7.30-7.22(m, 2H), 6.99 (d, J=2.7 Hz, 1H), 6.93 (dd, J=2.7, 4.3 Hz, 1H), 6.83 (d,J=5.5 Hz, 1H), 4.60-3.80 (br, 4H), 2.90-2.80 (m, 1H), 2.78-2.68 (m, 1H);MS: (ES) m/z calculated for C₂₂H₂₀FN₇O₂ [M+H]⁺ 434.2, found 434.

Example 65: Synthesis of ethyl 2-phenyl-2H-tetrazole-5-carboxylate

To a solution of aniline (0.58 g, 6.2 mmol) in 9.2 mL of EtOH/H₂O (1:1)at 0° C. was added 2.3 mL of conc. HCl followed by NaNO₂ (0.47 g, 6.8mmol, 1.1 eq). The mixture was stirred at 0° C. for 30 min. To aseparate solution of ethylglyoxalate (1.74 g, 17 mmol, 3.1 eq) in 34 mLof EtOH was added p-toluenesulfonylhydrazide (1.0 g, 5.4 mmol, 1 eq).The mixture was stirred at room temperature for 30 min thenconcentrated. The residue was redissolved in 34 mL of pyridine andcooled to 0° C. To the cooled solution was added the preformed diazoniumsalt. The reaction mixture was stirred at room temperature for 3 h andthen quenched with H₂O. The contents were extracted with ethyl acetateand the organic layer was dried with Na₂SO₄ and concentrated in vacuo.Purification by silica gel flash chromatography (hex:EtoAc 9:1) affordedethyl 2-phenyl-2H-tetrazole-5-carboxylate (0.84 g, 3.9 mmol, 71%).

Example 66: Synthesis of 2-phenyl-2H-tetrazole-5-carboxylic acid

To a solution of ethyl 2-phenyl-2H-tetrazole-5-carboxylate (0.84 g, 3.9mmol, 1 eq) in 7.6 mL of EtOH/H₂O (1.5:1) was added NaOH (0.31 g, 7.8mmol, 2 eq). The reaction mixture was heated at 60° C. for 30 min andwas then quenched with 0.65 mL of conc. HCl. The contents were filteredand washed with MeOH and the filtrate was dried with Na₂SO₄ andconcentrated in vacuo. Purification by silica gel flash chromatography(100% EtoAc) afforded 2-phenyl-2H-tetrazole-5-carboxylic acid (0.41 g,2.2 mmol, 55%).

Example 67: Synthesis of (S)-tert-butyl(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)carbamate

To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (80.2 g, 0.43mol, 1.1 eq) in 75 mL of diisopropylamine and 34 mL of NMP was addedportionwise 8-chloroimidazo[1,2-a]pyrazine (60 g, 0.39 mol, 1 eq). Thereaction mixture was heated at 100° C. for 4 h and was then diluted with1.2 L of ethyl acetate. The organic layer was washed with H₂O and brine,dried with Na₂SO₄ and concentrated to give (S)-tert-butyl(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)carbamate (111.7 g, 0.37mol, 94%).

Example 68: Synthesis of(S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine

To a solution of acetyl chloride (114 mL, 1.6 mol) in 290 mL of MeOH at0° C. was added a solution of (S)-tert-butyl(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)carbamate (111.7 g, 0.37mol) in 450 mL of MeOH. The reaction mixture was stirred at roomtemperature for 2 h then heated at 60° C. for 30 min. The product wasfiltered, washed with 200 mL of MeOH and dried in a vacuum oven toafforded (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (101.2 g,1.6 mol, 100%).

Example 69: Synthesis of(S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-2-phenyl-2H-tetrazole-5-carboxamide

To a solution of 2-phenyl-2H-tetrazole-5-carboxylic acid (0.10 g, 0.53mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine(0.15 g, 0.53 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.22mL, 0.58 mmol, 1.1 eq) and HATU (0.22 g, 0.58 mmol, 3 eq). The mixturewas stirred at room temperature for 1 h and was then concentrated andpurified by HPLC to afford(S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-2-phenyl-2H-tetrazole-5-carboxamide(0.10 g, 0.26 mmol, 49%). ¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J=7.0 Hz,2H), 8.06 (s, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.82 (s, 1H), 7.70-7.58 (m,3H), 7.19 (d, J=5.8 Hz, 1H), 5.00-4.90 (m, 1H), 4.80-3.80 (br, 4H),2.62-2.38 (m, 2H); MS: (ES) m/z calculated for C₁₈H₁₇N₉O [M+H]⁺ 376.2,found 376.

Example 70: Synthesis of methyl6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylate

A solution of 6-chloropyridazine-3-carboxylic acid (0.50 g, 3.2 mmol) in11 mL of SOCl₂ was heated at 75° C. for 2 h and was then concentratedand redissolved in 5 mL of MeOH. To the solution was added a 25%solution of sodium methoxide (0.75 mL, 3.5 mmol, 1.1 eq) in MeOH. Thereaction mixture was stirred at room temperature for 20 h and was thenquenched with H₂O and extracted with dichloromethane. Silica gel flashchromatography (EtOAc/MeOH 90:10) of the residue afford a 2:1 mixture ofthe 6-chloropyridazine-3-carboxylic acid and6-methoxypyridazine-3-carboxylic acid (0.160 g). To a solution of themixture of ester and chloride in 1.9 mL of p-dioxane was added 4-hydroxypiperidine (0.094 g, 93 mmol) followed by diisopropylethylamine (0.49mL, 2.8 mmol). The mixture was heated at 100° C. for 20 h thenconcentrated. Purification with silica gel flash chromatography affordedmethyl 6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylate (0.15 g, 63mmol).

Example 71: Synthesis of6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylic acid

To a solution of the ester (0.15 g, 0.63 mmol, 1 eq) in 2.5 mL ofEtOH/H₂O (1.5:1) was added NaOH (0.08 g, 1.9 mmol, 3 eq). The reactionmixture was heated at 50° C. for 1 h then quenched with 0.16 mL of conc.HCl. The contents were filtered and washed with MeOH and the filtratewas dried with Na₂SO₄ and concentrated in vacuo to afford6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylic acid.

Example 72: Synthesis of(S)-6-(4-hydroxypiperidin-1-yl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)pyridazine-3-carboxamide

To a solution of 6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylic acid(0.10 g, 0.45 mmol, 1 eq) and(S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.12 g, 0.44 mmol,1 eq) in 1 mL of DMSO was added triethylamine (0.19 mL, 0.49 mmol, 1.1eq) and HATU (0.19 g, 0.49 mmol, 3 eq). The mixture was stirred at roomtemperature for 30 min then concentrated and purified by HPLC to afford(S)-6-(4-hydroxypiperidin-1-yl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)pyridazine-3-carboxamide(0.12 g, 0.29 mmol, 66%). ¹H NMR (400 MHz, CD₃OD) δ 8.05 (s, 1H), 8.02(d, J=9.8 Hz, 1H), 7.94 (d, J=5.5 Hz, 1H), 7.81 (s, 1H), 7.5 (d, J=9.8Hz, 1H), 7.18 (d, J=5.8 Hz, 1H), 4.98-4.80 (m, 1H), 4.80-3.80 (br, 4H),4.20-4.10 (m, 2H), 4.00-3.90 (m, 1H), 3.55-3.45 (m, 2H), 2.60-2.35 (m,2H), 2.05-1.95 (m, 2H), 1.68-1.55 (m, 2H); MS: (ES) m/z calculated forC₂₀H₂₄N₈O₂ [M+H]⁺ 409.2, found 409.

Example 73: Synthesis of ethyl1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of 3,4-difluoroaniline (1 mL, 10 mmol) in 5.4 mL of H₂O at0° C. was added 2.8 mL of conc. HCl followed by NaNO₂ (1.0 g, 15 mmol,1.5 eq). The mixture was stirred at 0° C. for 30 min. An additionalamount of NaNO₂ (0.35 g, 5 mmol, 0.5 eq) was added and the mixture wasstirred for 1 h at 0° C. To a separate solution of NaOAc (8.9 g, 108mmol, 11 eq) in 13 mL EtOH/H₂O (12:1) was added ethyl-2-isocyanoacetate(1.1 mL, 10 mmol, 1 eq). The mixture was cooled to 0° C. and thediazonium salt mixture was added dropwise. After stirring for 1 h, thereaction was quenched with H₂O and extracted with EtOAc. The organiclayer was dried with Na₂SO₄ and concentrated in vacuo. Purification bysilica gel flash chromatography (hex:EtoAc 1:1) afforded ethyl1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylate (0.30 g, 1.3mmol, 13%).

Example 74: Synthesis of1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid

To a solution of ethyl1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylate (0.30 g, 1.2mmol, 1 eq) in 5 mL of EtOH/H₂O (1.5:1) was added NaOH (0.095 g, 2.4mmol, 2 eq). The reaction mixture was heated at 50° C. for 1 h thenquenched with 0.20 mL of conc. HCl. The contents were filtered andwashed with EtOAc then with MeOH and the MeOH filtrate was dried withNa₂SO₄ and concentrated in vacuo to afford1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.22 g, 0.98mmol, 84%).

Example 75: Synthesis of(S)-1-(3,4-difluorophenyl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylicacid (0.10 g, 0.44 mmol, 1 eq) and(S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.12 g, 0.44 mmol,1 eq) in 1 mL of DMSO was added triethylamine (0.19 mL, 0.49 mmol, 1.1eq) and HATU (0.19 g, 1.3 mmol, 3 eq). After stirring for 1 h at roomtemperature, the mixture was concentrated and purified by HPLC to afford(S)-1-(3,4-difluorophenyl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide(0.046 g, 0.11 mmol, 25%). ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.05(s, 1H), 7.96-7.88 (m, 2H), 7.81 (s, 1H), 7.75-7.71 (m, 1H), 7.52 (q,J=8.6 Hz, 1H), 7.19 (d, J=5.5 Hz, 1H), 4.98-4.80 (m, 1H), 4.80-3.80 (br,4H), 2.62-2.40 (m, 2H); MS: (ES) m/z calculated for C₁₉H₁₆F₂N₈O [M+H]⁺411.2, found 411.

Example 76: Synthesis of (S)-tert-butyl(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)carbamate

To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.50 g, 2.7mmol, 1 eq) and diisopropylamine (0.66 mL, 3.8 mmol, 1.4 eq) in 0.2 mLof NMP was added 4-chloropyrazolo[1,5-a]pyrazine (0.47 mL, 3.1 mmol, 1.1eq). After stirring for 1 h at room temperature, the mixture wasconcentrated and purified by silica gel column chromatography (100%EtOAc) to afford (S)-tert-butyl(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)carbamate (0.740 g, 2.4mmol, 91%).

Example 77: Synthesis of(S)-1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-amine

To a solution of (S)-tert-butyl(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)carbamate (0.74 g, 2.4mmol, 1 eq) in 3 mL of dioxane was added a solution of 4.0 M HCl indioxane (3 mL, 20 mmol, 4 eq). After heating for 3 h at 60° C., themixture was concentrated to afford(S)-1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-amine (0.670 g, 2.4mmol, 100%).

Example 78: Synthesis of(S)-1-phenyl-N-(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a solution of 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (0.093 g,0.49 mmol, 1.4 eq) and(S)-1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-amine (0.10 g, 0.36mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.20 mL, 1.4 mmol,2.6 eq) and HATU (0.21 g, 0.55 mmol, 1.5 eq). After stirring for 1 h atroom temperature, the mixture was concentrated and purified by HPLC toafford(S)-1-phenyl-N-(1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide(0.095 g, 0.25 mmol, 52%). ¹H NMR (400 MHz, CD₃OD) δ 9.13 (s, 1H), 8.16(d, J=2.4 Hz, 1H), 8.09 (d, J=5.8 Hz, 1H), 7.86 (d, J=7.8 Hz, 2H),7.60-7.46 (m, 4H), 7.19 (d, J=5.5 Hz, 1H), 4.95-4.80 (m, 1H), 4.78-3.80(br, 4H), 2.62-2.40 (m, 2H); MS: (ES) m/z calculated for C₁₉H₁₈N₈O[M+H]⁺ 375.2, found 375.

Example 79: Synthesis of (S)-tert-butylN-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)carbamate

To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.91 g, 4.9mmol, 1 eq) in 2.6 mL of DIPEA was added 1-chloropyrrolo[1,2-a]pyrazine(0.75 g, 4.9 mmol, 1 eq) and 1 drop of 1-butyl-3-methylimidazoliumtetrafluorborate. After heating for 3 h at 110° C., the mixture wasconcentrated and purified by silica gel flash chromatography (100%EtOAc) to afford (S)-tert-butylN-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)carbamate (0.88 g, 2.9mmol, 59%).

Example 80: Synthesis of(S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine

To a solution of (S)-tert-butylN-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)carbamate (0.88 g, 2.9mmol, 1 eq) in 3.6 mL of dioxane was added a solution of 4.0 M HCl indioxane (3.6 mL, 14.5 mmol, 5 eq). After heating for 1 h at 60° C., themixture was concentrated to afford(S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.79 g, 2.9 mmol,100%).

Example 81: Synthesis of(S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of 5-bromopyrimidine-2-carboxylic acid (2.0 g, 9.9 mmol, 1eq) and (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (2.7 g, 9.9mmol, 1 eq) in 20 mL of DMSO was added triethylamine (5.4 mL, 39 mmol,3.9 eq) and HATU (4.1 g, 11 mmol, 1.1 eq). After stirring for 1 h atroom temperature, the mixture was concentrated and purified by silicagel flash chromatography (EtoAc:MeOH 2:3) to produce(S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(5.0 g, 1.3 mmol, 13%).

Example 82: Synthesis of(S)-5-(cyclopent-1-en-1-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of(S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.10 g, 0.27 mmol, 1 eq) in 1.8 mL of DMF was added2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g,0.77 mmol, 2.8 eq), followed by K₂CO₃ (0.18 g, 1.3 mmol, 4.8 eq) in 0.2mL of H₂O and Pd(dppf)Cl₂ (0.02 g, 0.03 mmol, 0.09 eq). After heatingfor 1 h at 120° C. the mixture was concentrated and purified by silicagel flash chromatography (EtoAc:MeOH 1:1) followed by HPLC to afford(S)-5-(cyclopent-1-en-1-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.070 g, 0.19 mmol, 69%).

Example 83: Synthesis of(S)-5-cyclopentyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of(S)-5-(cyclopent-1-en-1-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.07 g, 0.19 mmol, 1 eq) in 1 mL of MeOH was added 10% Pd/C (0.02 g,0.02 mmol, 0.1 eq). The reaction mixture was equipped with a H₂ balloonand stirred for 3 hr at room temperature. The contents were filtered andthe purified by HPLC to afford(S)-5-cyclopentyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.005 g, 0.013 mmol, 7%). ¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 2H), 7.78(q, J=1.1 Hz, 1H), 7.73 (d, J=5.8 Hz, 1H), 7.57 (d, J=3.9 Hz, 1H), 6.94(dd, J=2.7, 4.7 Hz, 1H), 6.86 (d, J=5.9 Hz, 1H), 5.00-4.80 (m, 1H),4.50-3.50 (br, 4H), 3.20-3.10 (m, 1H), 2.60-2.48 (m, 1H), 2.48-2.38 (br,1H), 2.22-2.12 (m, 2H), 1.95-1.60 (m, 6H); MS: (ES) m/z calculated forC₂₁H₂₄N₆O [M+H]⁺ 377.2, found 377.

Example 84: Synthesis of(S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide

To a solution of 6-methylquinazoline-2-carboxylic acid (0.040 g, 0.21mmol, 1.2 eq) and(S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine (0.49 g,0.18 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.10 mL, 0.7mmol, 4 eq) and HATU (0.075 g, 0.20 mmol, 1.1 eq). After stirring for 1h at room temperature, the mixture was concentrated and purified by HPLCto afford(S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide(0.028 g, 0.07 mmol, 42%). ¹H NMR (400 MHz, DMSO) δ 9.62 (s, 1H), 9.31(t, J=3.9 Hz, 1H), 8.08-8.00 (m, 2H), 8.00-7.92 (m, 1H), 7.85 (d, J=5.1Hz, 1H), 7.29 (d, J=5.0 Hz, 1H), 4.82-4.70 (m, 1H), 4.70-3.60 (br, 4H),2.56 (s, 3H), 2.40-2.20 (br, 2H); MS: (ES) m/z calculated for C₁₉H₁₈N₈O[M+H]⁺375.2, found 375.

Example 85: Synthesis of(S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide

To a solution of 6-methylquinazoline-2-carboxylic acid (0.040 g, 0.21mmol, 1.2 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine(0.49 g, 0.18 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.10mL, 0.7 mmol, 4 eq) and HATU (0.075 g, 0.20 mmol, 1.1 eq). Afterstirring for 1 h at room temperature, the mixture was concentrated andpurified by HPLC to afford(S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide(0.057 g, 0.15 mmol, 86%). ¹H NMR (400 MHz, CD₃OD) δ 9.48 (s, 1H), 8.02(d, J=1.6 Hz, 2H), 7.98-7.88 (m, 3H), 7.78 (s, 1H), 7.17 (d, J=5.8 Hz,1H), 5.00-3.80 (br, 4H), 2.60 (s, 3H), 2.65-2.40 (br, 2H); MS: (ES) m/zcalculated for C₂₀H₁₉N₇O [M+H]⁺ 374.2, found 374.

Example 86: Synthesis of ethyl2-(4-chloro-2-formyl-anilino)-2-oxo-acetate

To a solution of 2-amino-5-chloro-benzaldehyde (0.10 g, 0.65 mmol, 1 eq)in 1.6 mL of DCM at 0° C. was added ethylchloroacetate (0.09 mL, 0.85mmol, 1.3 eq) and pyridine (0.16 mL, 2.0 mmol, 3 eq). After stirring atroom temperature for 1 h, the reaction was quenched with H₂O andextracted with ethyl acetate. The organic layer was washed with 10%citric acid followed by saturated NaHCO₃ then dried with Na₂SO₄ andconcentrated. The residue was purified on silica gel columnchromatography (hex:EtoAc 3:2) to provide ethyl2-(4-chloro-2-formyl-anilino)-2-oxo-acetate (0.14 g, 0.55 mmol, 84%).

Example 87: Synthesis of ethyl 6-chloroquinazoline-2-carboxylate

To a solution of ethyl 2-(4-chloro-2-formyl-anilino)-2-oxo-acetate (0.14g, 0.55 mmol, 1 eq) in 5.5 mL of acetic acid was added ammonium acetate(0.42 g, 5.4 mmol, 10 eq). After heating at 115° C. for 1 h, the mixturewas concentrated then diluted with H₂O and extracted with ethyl acetate.The organic layer was concentrated and the residue was purified onsilica gel column chromatography (hex:EtoAc 3:2) to give ethyl6-chloroquinazoline-2-carboxylate (0.11 g, 0.48 mmol, 88%).

Example 88: Synthesis of (S)-tert-butyl3-(6-chloroquinazoline-2-carboxamido)pyrrolidine-1-carboxylate

To a solution of ethyl 6-chloroquinazoline-2-carboxylate (0.200 g, 0.85mmol, 1 eq) in 0.42 mL of NMP was added (S)-tert-butyl3-aminopyrrolidine-1-carboxylate (0.16 g, 0.86 mmol, 1 eq) anddiisopropylethylamine (0.6 mL, 3.4 mmol, 4 eq). After stirring at 150°C. for 20 h, the mixture was concentrated and purified via silica gelflash chromatography to provide (S)-tert-butyl3-(6-chloroquinazoline-2-carboxamido)pyrrolidine-1-carboxylate (0.08 g,0.21 mmol, 25%).

Example 89: Synthesis of(S)-6-chloro-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)quinazoline-2-carboxamide

To a solution of (S)-tert-butyl3-(6-chloroquinazoline-2-carboxamido)pyrrolidine-1-carboxylate (0.086 g,0.23 mmol, 1 eq) in 1 mL of p-dioxane was added a solution of 4.0 M HClin dioxane (0.29 mL, 1.2 mmol, 5 eq). After stirring at 60° C. for 1 h,the mixture was concentrated to provide(S)-6-chloro-N-(pyrrolidin-3-yl)quinazoline-2-carboxamide which wascarried on without further purification.

To a solution of the crude amine in 0.16 mL of diisopropylethylamine wasadded 1-chloropyrrolo[1,2-a]pyrazine (0.047 g, 0.31 mmol) followed by 1drop of 1-butyl-3-methylimidazolium tetrafluorborate. The reaction washeated at 90° C. for 20 h. Purification of the residue by HPLC afforded(S)-6-chloro-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)quinazoline-2-carboxamide(0.05 g, 0.013 mmol, 6%). ¹H NMR (400 MHz, CD₃OD) δ 9.60 (s, 1H), 8.26(s, 1H), 8.17 (d, J=9.1 Hz, 1H), 8.07 (dd, J=1.8, 9.1 Hz, 1H), 7.76 (d,J=1.5 Hz, 1H), 7.72 (d, J=5.8 Hz, 1H), 7.57 (s, 1H), 6.93 (m, 1H), 6.85(d, J=5.8 Hz, 1H), 5.06-4.84 (m, 1H), 4.82-3.60 (br, 4H), 2.65-2.40 (br,2H); MS: (ES) m/z calculated for C₂₀H₁₇ClN₆O [M+H]⁺ 393.2, found 393.

Example 90: Synthesis of(S)-5-methyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of 5-methylpyrimidine-2-carboxylic acid (0.03 g, 0.22mmol, 1 eq) and (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine(0.060 g, 0.22 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.12mL, 0.86 mmol, 4 eq) and HATU (0.09 g, 0.24 mmol, 1.1 eq). Afterstirring for 1 h at room temperature, the mixture was concentrated andpurified by HPLC to afford(S)-5-methyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.029 g, 0.09 mmol, 41%). ¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 2H), 7.76(s, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.54 (s, 1H), 6.91 (s, 1H), 6.85 (d,J=5.8 Hz, 1H), 5.00-3.60 (br, 5H), 2.65-2.30 (br, 2H), 2.40 (s, 3H); MS:(ES) m/z calculated for C₁₇H₁₈N₆O [M+H]+ 323.2, found 323.

Example 91: Synthesis of(S)—N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-5-vinylpyrimidine-2-carboxamide

To a solution of(S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.10 g, 0.26 mmol, 1 eq) in 1 mL of DMF was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.13 g, 0.84 mmol, 3.2eq), followed by K₂CO₃ (0.18 g, 1.3 mmol, 5 eq) in 0.2 mL of H₂O andPd(dppf)Cl₂ (0.02 g, 0.02 mmol, 0.1 eq). After heating for 1 h at 120°C. the mixture was concentrated and purified by silica gel columnchromatography (EtoAc:MeOH 1:1) followed by HPLC to afford(S)—N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-5-vinylpyrimidine-2-carboxamide(0.040 g, 0.12 mmol, 46%).

Example 92: Synthesis of(S)-5-ethyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of(S)—N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-5-vinylpyrimidine-2-carboxamide(0.04 g, 0.12 mmol, 1 eq) in 1 mL of MeOH was added 10% Pd/C (0.013 g,0.01 mmol, 0.1 eq). The reaction mixture was equipped with a H₂ balloonand stirred for 1 hr at room temperature. The contents were filtered andthe purified by HPLC to afford(S)-5-ethyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.009 g, 0.25 mmol, 22%). ¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 2H), 7.76(m, 1H), 7.71 (d, J=5.8 Hz, 1H), 7.54 (s, 1H), 6.92 (dd, J=2.6, 4.4 Hz,1H), 6.84 (d, J=5.5 Hz, 1H), 5.00-3.60 (br, 5H), 2.81 (q, J=7.4 Hz, 2H),2.65-2.30 (br, 2H), 1.33 (t, J=7.4 Hz, 3H); MS: (ES) m/z calculated forC₁₇H₁₈N₆O [M+H]⁺ 337.2, found 337.

Example 93: Synthesis of(S)-5-cyclopropyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of(S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.25 g, 0.65 mmol, 1 eq) in 2 mL of toluene was added2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.16 g, 1.86mmol, 2.8 eq), followed by PCy₃ (0.033 g, 0.11 mmol, 0.2 eq), K₃PO₄(0.48 g, 2.3 mmol, 3.5 eq) in 0.1 mL of H₂O and Pd(OAc)₂ (0.013 g, 0.06mmol, 0.1 eq). After heating for 1 h at 120° C. the mixture was filteredand purified by HPLC to afford(S)-5-cyclopropyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.009 g, 0.026 mmol, 4%). ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 2H), 7.76(m, 1H), 7.71 (d, J=5.4 Hz, 1H), 7.54 (s, 1H), 6.92 (dd, J=2.6, 4.4 Hz,1H), 6.84 (d, J=5.5 Hz, 1H), 5.00-3.60 (br, 5H), 2.65-2.30 (br, 2H),2.07-2.02 (m, 1H), 1.23-1.18 (m, 2H), 0.96-0.91 (m, 2H); MS: (ES) m/zcalculated for C₁₉H₂₀N₆O [M+H]⁺ 349.2, found 349.

Example 94: Synthesis of(S)-5-(4-fluorophenyl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of(S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.036 g, 0.093 mmol, 1 eq) in 1.8 mL of DMF was added(4-fluorophenyl)boronic acid (0.10 g, 0.71 mmol, 7.7 eq), followed byK₂CO₃ (0.18 g, 1.3 mmol, 14 eq) in 0.2 mL of H₂O and Pd(dppf)Cl₂ (0.02g, 0.03 mmol, 0.3 eq). After heating for 1 h at 120° C. the mixture wasfiltered and purified by HPLC to afford(S)-5-(4-fluorophenyl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.014 g, 0.035 mmol, 37%). ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 2H), 7.83(m, 3H), 7.71 (d, J=5.4 Hz, 1H), 7.56 (s, 1H), 7.31 (t, J=8.5 Hz, 2H),6.92 (s, 1H), 6.85 (d, J=5.9 Hz, 1H), 5.00-3.60 (br, 5H), 2.65-2.30 (br,2H); MS: (ES) m/z calculated for C₂₂H₁₉FN₆O [M+H]⁺ 403.2, found 403.

Example 95: Synthesis of(S)-5-(prop-1-en-2-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of(S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.075 g, 0.19 mmol, 1 eq) in 1.8 mL of DMF was added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.10 g, 0.6mmol, 3 eq), followed by K₂CO₃ (0.14 g, 0.99 mmol, 5 eq) in 0.2 mL ofH₂O and Pd(dppf)Cl₂ (0.02 g, 0.02 mmol, 0.1 eq). After heating for 2 hat 120° C. the mixture was filtered, concentrated and carried forward tothe next step.

Example 96: Synthesis of(S)-5-isopropyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide

To a solution of(S)-5-(prop-1-en-2-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.090 g, 0.26 mmol, 1 eq) in 1 mL of MeOH was added 10% Pd/C (0.027 g,0.03 mmol, 0.1 eq). The reaction mixture was equipped with a H₂ balloonand stirred for 1 hr at room temperature. The contents were filtered andthe purified by HPLC to afford(S)-5-isopropyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(0.048 g, 0.14 mmol, 53%). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (s, 2H), 7.76(s, 1H), 7.71 (d, J=5.8 Hz, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 6.84 (d,J=5.9 Hz, 1H), 5.00-3.60 (br, 5H), 3.18-3.00 (m, 1H), 2.65-2.30 (br,2H), 1.36 (d, J=7.0 Hz, 6H); MS: (ES) m/z calculated for C₁₉H₂₂N₆O[M+H]⁺ 351.2, found 351.

Example 97: Synthesis of ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate

To a solution of 1-fluoro-4-iodo-benzene (1.47 g, 6.6 mmol, 1.3 eq) andethyl 1H-pyrazole-3-carboxylate (0.71 g, 5.1 mmol, 1 eq) in 15 mL oftoluene was added CuI (0.19 g, 1.0 mmol, 0.2 eq),trans-N,—N-dimethylcyclohexane 1,2-diamine (0.4 mL, 2.5 mmol, 0.2 eq),and potassium carbonate (1.4 g, 10 mmol, 2 eq). The reaction mixture washeated at 110° C. for 2 d then filtered and concentrated. The residuewas purified by silica gel column chromatography (hex:EtoAc 4:1) toafford ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate (0.92 g, 3.9 mmol,77%).

Example 98: Synthesis of 1-(4-fluorophenyl)pyrazole-3-carboxylic acid

To a solution of ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate (0.92 g,3.9 mmol, 1 eq) in 18 mL of EtOH/H₂O (1.5:1) was added NaOH (0.47 g,11.8 mmol, 3 eq). The reaction mixture was heated at 50° C. for 1 h thenquenched with H₂O and extracted with ethyl acetate. The combined organiclayers were concentrated and purified by silica gel columnchromatography (EtoAc:MeOH 3:1) to provide1-(4-fluorophenyl)pyrazole-3-carboxylic acid (0.42 g, 2.0 mmol, 52%).

Example 99: Synthesis of(S)-1-(4-fluorophenyl)-N-(1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-1H-pyrazole-3-carboxamide

To a solution of 1-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (0.04g, 0.19 mmol, 1.5 eq) in 1 mL of DCM was added(S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.036 g,0.13 mmol, 1 eq), propylphosphonic anhydride (0.3 mL, 0.47 mmol, 2.5eq), and N-methylmorpholine (0.15 mL, 1.36 mmol, 10.5 eq). The reactionmixture was stirred at room temperature for 1 h then quenched with H₂Oand extracted with ethyl acetate. The combined organic layers wereconcentrated and purified by HPLC to afford(S)-1-(4-fluorophenyl)-N-(1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-1H-pyrazole-3-carboxamide(0.030 g, 0.074 mmol, 57%). ¹H NMR (400 MHz, CDCCl₃) δ 7.91 (d, J=7.3Hz, 1H), 7.82 (s, 1H), 7.68 (dd, J=4.4, 8.8 Hz, 2H), 7.33 (d, J=4.8 Hz,1H), 7.19 (t, J=8.8 Hz, 3H), 7.00 (m, 2H), 6.50 (s, 1H), 4.75 (s, 1H),3.90-3.56 (m, 4H), 2.57 (s, 3H), 2.42-2.38 (m, 1H), 2.02-1.80 (m, 1H);MS: (ES) m/z calculated for C₂₂H₂₁FN₆O [M+H]⁺405.2, found 405.

Example 100: Synthesis of(S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-1-phenyl-1H-1,2,4-triazole-3-carboxamide

a) A mixture of 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (620 mg, 4.0mmol) and (S)-tert-butyl pyrrolidin-3-yl carbamate (1.2 g, 6.5 mmol) indiethylisopropyl amine (3 mL) was heated to 120° C. for 2 h. Aftercooling to room temperature, the mixture was diluted with 10% MeOH inEtOAc and washed with saturated aqueous solutions of KH₂PO₄ and NaHCO₃,followed by brine. The organic layer was concentrated in vacuo and theresidue purified by flash chromatography (SiO₂, 2 to 5% MeOH in CH₂Cl₂as eluent) to give the desired compound as a foam (1.15 g, 95% yield,which was used directly for the next step). MS: (ES) m/z 305.2 (M+H⁺).

b) The above Boc-amine was dissolved in CH₂Cl₂ (4 mL) and MeOH (3 mL) atroom temperature, followed by addition of 4 N HCl in dioxane (9 mL, 36mmol). The mixture was stirred at room temperature for 2 h. Theresulting suspension was diluted with EtOAc. Filtration and air-dryinggave the desired compound as an off-white solid (1.05 g, quantitative,which was used directly for the next step). MS: (ES) m/z 205.1 (M+H⁺).

c) To a suspension of the above(S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (90 mg, 0.32 mmol),1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (58 mg, 0.30 mmol) in DMF(5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed byHATU (120 mg, 0.31 mmol). The resulting solution was stirred at roomtemperature for 1 h. The reaction mixture was diluted with ethyl acetateand washed with saturated aqueous solutions of KH₂PO₄ and NaHCO₃,followed by brine. The organic layer was concentrated in vacuo and theresidue purified by reverse phase HPLC (acetonitrile-H₂O with 0.1% TFAas eluent) to give 23 mg of the title compound (20% yield) as whitesolid. ¹H NMR (400 MHz, d6-DMSO) δ 2.10-2.38 (two sets of m, 2H),3.50-4.60 (br, 4H), 4.65 (m, 1H), 7.29 (d, J=4.4 Hz, 1H), 7.46 (t, J=7.3Hz, 1H), 7.59 (t, J=7.3 Hz, 2H), 7.75 (d, J=4.7 Hz, 1H), 7.90 (d, J=8.0Hz, 2H), 9.00 (d, J=7.0H, 1H), 9.20 (s, 1H), 9.40 (s, 1H). MS: (ES) m/zcalculated for C₁₈H₁₇N₉O [M+H]⁺ 376.2, found 376.2.

Example 101: Synthesis of(S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of(S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (63 mg, 0.23 mmol),1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.2 mmol)in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol),followed by HATU (76 mg, 0.2 mmol). The resulting solution was stirredat room temperature for 1 h. The reaction mixture was diluted with ethylacetate and washed with saturated aqueous solutions of KH₂PO₄ andNaHCO₃, followed by brine. The organic layer was concentrated in vacuoand the residue purified by reverse phase HPLC (acetonitrile-H₂O with0.1% TFA as eluent) to give 32 mg of the title compound (40% yield) aswhite solid. MS: (ES) m/z found 394.2.

Example 102: Synthesis of(S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

To a suspension of(S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (94 mg, 0.34 mmol),1-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (63 mg, 0.3 mmol) inDMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followedby HATU (120 mg, 0.31 mmol). The resulting solution was stirred at roomtemperature for 1 h. The reaction mixture was diluted with ethyl acetateand washed with saturated aqueous solutions of KH₂PO₄ and NaHCO₃,followed by brine. The organic layer was concentrated in vacuo and theresidue purified by reverse phase HPLC (acetonitrile-H₂O with 0.1% TFAas eluent) to give 50 mg of the title compound (42% yield) as a whitesolid. MS: (ES) m/z found 393.2.

Example 103: Synthesis of(S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-1-phenyl-1H-imidazole-4-carboxamide

To a suspension of(S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (109 mg, 0.4 mmol) and1-phenyl-1H-imidazole-4-carboxylic acid (76 mg, 04 mmol) in DMF (5 mL)was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (160mg, 0.41 mmol). The resulting solution was stirred at room temperaturefor 1 h. The reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous solutions of KH₂PO₄ and NaHCO₃, followed bybrine. The organic layer was concentrated in vacuo and the residuepurified by reverse phase HPLC (acetonitrile-H₂O with 0.1% TFA aseluent) to give 100 mg of the title compound (67% yield) as a whitesolid. MS: (ES) m/z found 375.1.

Example 104: Synthesis of(S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-5-isopropylpyrimidine-2-carboxamide

a) To a suspension of the ethyl 5-bromopyrimidine-2-carboxylate (700 mg,3 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.5g, 9 mmol), and K₂CO₃ (2.1 g, 15 mmol) in DMF (5 mL) and water (1 mL),was added Pd(dppfCl2) (250 mg, 0.3 mmol). The resulting mixture wasdegassed (N₂) for 2 min and then heated to heated to 120° C. for 1 h.After cooling to room temperature, the reaction mixture was diluted withMeOH and filtered through celite. The filtrate was used directly fornext step. MS: (ES) m/z 165.2 (M+H⁺).

b) To the above filtrate was added 10% Pd/C (wet, 300 mg) and themixture stirred under a H₂-balloon overnight. Solid was filtered off.The filtrate was diluted with CH₂Cl₂ and washed with 1N HCl and brine.The organic layer was concentrated in vacuo to give 300 mg of the titlecompound (60% yield) as light brown solid. MS: (ES) m/z 167.2 (M+H⁺).

c) To a suspension of═(S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (84 mg, 0.3 mmol), 5-isopropylpyrimidine-2-carboxylicacid (51 mg, 0.3 mmol) in DMF (5 mL) was added diethylisopropyl amine(650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resultingsolution was stirred at room temperature for 1 h. The reaction mixturewas diluted with ethyl acetate and washed with saturated aqueoussolutions of KH₂PO₄ and NaHCO₃, followed by brine. The organic layer wasconcentrated in vacuo and the residue purified by reverse phase HPLC(acetonitrile-H₂O with 0.1% TFA as eluent) to give 6 mg of the titlecompound (5% yield) as a white solid. MS: (ES) m/z found 353.1.

Example 105: Synthesis of(S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-5-isopropylpyrimidine-2-carboxamide

To a suspension of (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (84 mg, 0.3 mmol) and5-isopropylpyrimidine-2-carboxylic acid (85 mg, 0.5 mmol) in DMF (5 mL)was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (190mg, 0.5 mmol). The resulting solution was stirred at room temperaturefor 1 h. The reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous solutions of KH₂PO₄ and NaHCO₃, followed bybrine. The organic layer was concentrated in vacuo and the residuepurified by reverse phase HPLC (acetonitrile-H₂O with 0.1% TFA aseluent) to give 35 mg of the title compound (32% yield) as a whitesolid. MS: (ES) m/z found 352.1.

Example 106: Synthesis of(±)-N-(3-(hydroxymethyl)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-5-isopropylpyrimidine-2-carboxamide

To a suspension of(±)-(3-amino-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)methanolhydrochloride salt (62 mg, 0.2 mmol) and5-isopropylpyrimidine-2-carboxylic acid (40 mg, 0.22 mmol) in DMF (5 mL)was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (76mg, 0.2 mmol). The resulting solution was stirred at room temperaturefor 1 h. The reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous solutions of KH₂PO₄ and NaHCO₃, followed bybrine. The organic layer was concentrated in vacuo and the residuepurified by reverse phase HPLC (acetonitrile-H₂O with 0.1% TFA aseluent) to give 25 mg of the title compound (32% yield) as a whitesolid. MS: (ES) m/z found 381.1.

Example 107: Synthesis of(S)—N-(1-([1,2,4]triazolo[1,5-a]pyrazin-8-yl)pyrrolidin-3-yl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

a) A mixture of 2-aminopyrazine (1.9 g, 20 mmol) andN,N-dimethylformamide dimethyl acetal (2.62 g, 22 mmol) in toluene washeated to reflux for 6 h. The solvent was evaporated and residue wasused directly for the next step.

b) To a solution of the above in MeOH (30 mL) cooled in an ice-bath, wasadded NaOAc trihydrate (3.65 g, 25 mmol) followed by slowly addition ofNH₂OH.HCl (1.74 g, 25 mmol). The mixture was allowed slowly warm up toroom temperature over 6 h and was then diluted with DCM and with 20% 7 Nammonia solution in MeOH. Solid was filtered off and the filtrate wasconcentrated in vacuo and the residue was triturated with EtOH.Filtration and air-drying gave the desired compound as an off-whitesolid (1.9 g, 69% yield, which was used directly for the next step). MS:(ES) m/z 139.1 (M+H⁺).

c) A mixture of the above solid (1.9 g, 13.8 mmol) and PPA (15 mL) washeated to 90° C. for 6 h and was then diluted with ice-water and the pHwas adjusted to 8 with aqueous ammonia solution and NaHCO₃. The mixturewas then extracted with 10% MeOH in CH₂Cl₂. The organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo to give the desiredcompound as off-white solid (1.2 g, 75% yield, which was used directlyfor the next step). MS: (ES) m/z 121.1 (M+H⁺).

d) To a mixture of the above solid (600 mg, 5 mmol) in AcOH was addedslowly a 30% aqueous H₂O₂ solution (1.8 mL, 19 mmol) at roomtemperature. The resulting mixture was heated to 90° C. for 6 h and thenwas poured into ice-water and the pH was adjusted to 8 with 1 N NaOH.The mixture was extracted with 10% MeOH in CH₂Cl₂. The organic layer wasdried (Na₂SO₄), filtered and concentrated in vacuo to give the desiredcompound as a foam (120 mg, 17% yield, which was used directly for thenext step). MS: (ES) m/z 137.2.1 (M+H⁺).

e) A mixture of the above foam (120 mg, 0.9 mmol) and POCl₃ (5 mL) washeated to 120° C. for 6 h and then concentrated in vacuo. The residuewas diluted with EtOAc and washed with saturated aqueous NaHCO₃. Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo togive the desired compound as tan solid (50 mg, 36% yield, which was useddirectly for the next step). MS: (ES) m/z 155.0 (M+H⁺).

f) A mixture of the above 8-chloro-[1,2,4]triazolo[1,5-a]pyrazine (50mg, 0.32 mmol) and (S)-tert-butyl pyrrolidin-3-yl carbamate (100 mg,0.53 mmol) in diethylisopropyl amine (2 mL) was heated to 120° C. for 2h. After cooling to room temperature, the mixture was diluted with 10%MeOH in EtOAc and washed with saturated aqueous solutions of KH₂PO₄ andNaHCO₃, followed by brine. The organic layer was concentrated in vacuoand the residue purified by flash chromatography (SiO₂, 2 to 5% MeOH inCH₂Cl₂ as eluent) to give the desired compound as a foam (80 mg, 82%yield, which was used directly for the next step). MS: (ES) m/z 305.2(M+H⁺).

g) The above Boc-amine was dissolved in CH₂Cl₂ (3 mL) and MeOH (1 mL) atroom temperature, followed by addition of 4 N HCl in dioxane (4 mL, 16mmol). The mixture was stirred at room temperature for 2 h and then wasconcentrated in vacuo to give the desired compound as a light yellowsolid (72 mg, quantitative, which was used directly for the next step).MS: (ES) m/z 205.1 (M+H⁺).

h) To a suspension of the above amine hydrochloride salt (60 mg, 0.22mmol) and 1-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (46 mg, 0.22mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol),followed by HATU (86 mg, 0.22 mmol). The resulting solution was stirredat room temperature for 1 h. The reaction mixture was diluted with ethylacetate and washed with saturated aqueous solutions of KH₂PO₄ andNaHCO₃, followed by brine. The organic layer was concentrated in vacuoand the residue purified by silica gel flash chromatography (2 to 5%MeOH in CH₂Cl₂ as eluent) followed by reverse phase HPLC(acetonitrile-H₂O with 0.1% TFA as eluent) to give 28 mg of the titlecompound (32% yield) as a white solid. ¹H NMR (400 MHz, d6-DMSO) δ2.05-2.38 (two sets of m, 2H), 3.60-4.58 (br, 4H), 4.63 (m, 1H), 6.89(d, J=2.2 Hz, 1H), 7.36 (t, J=6.6 Hz, 2H), 7.29 (d, J=4.4 Hz, 1H), 7.46(t, J=7.3 Hz, 1H), 7.57 (d, J=4.4 Hz, 1H), 7.97-7.92 (m, 2H) (checkF-coupling), 8.13 (d, J=4.4 Hz, 1H), 8.46 (s, 1H), 8.52 (d, J=2.6 Hz,1H), δ 8.55 (d, J=7.0 Hz, 1H). MS: (ES) m/z calculated for C₁₉H₁₇FN₈O[M+H]⁺ 393.2, found 393.

Example 108: Synthesis of(S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1-phenyl-1H-1,2,4-triazole-3-carboxamide

a) A mixture of 8-chloroimidazo[1,2-a]pyrazine (500 mg, 3.25 mmol) and(S)-tert-butyl pyrrolidin-3-yl carbamate (1.0 g, 5.38 mmol) indiethylisopropyl amine (3 mL) was heated to 120° C. for 3 h. Aftercooling to room temperature, the mixture was diluted with 10% MeOH inEtOAc and washed with saturated aqueous solutions of KH₂PO₄ and NaHCO₃,followed by brine. The organic layer was concentrated in vacuo and theresidue purified by flash chromatography (SiO₂, 2 to 5% MeOH in CH₂Cl₂as eluent) to give the desired compound as a foam (985 mg, quantitative,which was used directly for the next step). MS: (ES) m/z 304.1 (M+H⁺).

b) The above Boc-amine was dissolved in CH₂Cl₂ (5 mL) and MeOH (3 mL) atroom temperature, followed by addition of 4 N HCl in dioxane (9 mL, 16mmol). The mixture was stirred at room temperature for 2 h. Theresulting suspension was diluted with EtOAc. Filtration and air-dryinggave the desired compound as an off-white solid (895 mg, quantitative,which was used directly for the next step). MS: (ES) m/z 204.1 (M+H⁺).

c) To a suspension of the above(S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt(84 mg, 0.3 mmol) and 1-phenyl-TH-1,2,4-triazole-3-carboxylic acid (57mg, 0.3 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution wasstirred at room temperature for 1 h. The reaction mixture was dilutedwith ethyl acetate and washed with saturated aqueous solutions of KH₂PO₄and NaHCO₃, followed by brine. The organic layer was concentrated invacuo and the residue purified by silica gel flash chromatography (2 to5% MeOH in CH₂Cl₂ as eluent) followed by reverse phase HPLC(acetonitrile-H₂O with 0.1% TFA as eluent) to give 60 mg of the titlecompound (54% yield) as white solid. MS: (ES) m/z calculated forC₁₉H₁₈N₈O [M+H]⁺ 375.2, found 375.2.

Example 109: Synthesis of(S)-1-(4-fluorophenyl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (55 mg, 0.2 mmol) and1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.2 mmol)in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol),followed by HATU (76 mg, 0.2 mmol). The resulting solution was stirredat room temperature for 1 h. The reaction mixture was diluted with ethylacetate and washed with saturated aqueous solutions of KH₂PO₄ andNaHCO₃, followed by brine. The organic layer was concentrated in vacuoand the residue purified by reverse phase HPLC (acetonitrile-H₂O with0.1% TFA as eluent) to give 45 mg of the title compound (57% yield) aswhite solid. MS: (ES) m/z found 393.1.

Example 110: Synthesis of(S)-1-(3-fluorophenyl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-aminehydrochloride salt (84 mg, 0.3 mmol) and1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (63 mg, 0.3 mmol)in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol),followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirredat room temperature for 1 h. The reaction mixture was diluted with ethylacetate and washed with saturated aqueous solutions of KH₂PO₄ andNaHCO₃, followed by brine. The organic layer was concentrated in vacuoand the residue purified by reverse phase HPLC (acetonitrile-H₂O with0.1% TFA as eluent) to give 88 mg of the title compound (75% yield) as awhite solid. MS: (ES) m/z found 393.1.

Example 111: Synthesis of(S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-5-phenyl-1,2,4-oxadiazole-3-carboxamide

a) To a mixture of ethyl 2-oximinoxamate (1.32 g, 10 mmol) anddiethylisopropyl amine (4 mL, 23 mmol) in CH₂Cl₂ (30 mL) at −15° C. wasadded slowly benzoyl chloride (1.41 g, 10 mmol). over 2 h. The mixturewas allowed slowly warm up to room temperature over 5 h and then pouredinto ice-water and extracted with CH₂Cl₂. The organic layer was dried(Na₂SO₄), filtered and was concentrated to give the desired compound asa white solid (2.36 g, quantitative, which was used directly for thenext step).

b) A mixture of the above solid (1.2 g, 5 mmol) and pyridine (6 mL) washeated to at 120° C. for 10 h. After evaporation of the solvent, theresidue was purified by silica gel flash chromatography (10 to 25% EtOAcin hexane as eluent) to give the desired compound as an off-white solid(900 mg, 83% yield, which was used directly for the next step). MS: (ES)m/z 219.1 (M+H⁺).

c) To a mixture of the above ester (900 mg, 4.1 mmol), MeOH (5 mL), THF(5 mL) and DI H₂O (5 mL) was added LiOH monohydrate (420 mg, 10 mmol).The resulting mixture was stirred at room temperature for 3 h. Themixture was then diluted with ice-water, pH adjusted to 3 with 1 N HCl,and mixture was then extracted with 10% MeOH in CH₂Cl₂. The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo give thedesired compound as an off-white solid (900 mg, 83% yield, which wasused directly for the next step). MS: (ES) m/z 219.1 (M+H⁺).

d) To a suspension of the above 5-phenyl-1,2,4-oxadiazole-3-carboxylicacid (58 mg, 0.3 mmol),(S)-1-([1,2,4]triazolo[1,5-a]pyrazin-5-yl)pyrrolidin-3-aminehydrochloride salt (90 mg, 0.32 mmol) in DMF (5 mL) was addeddiethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31mmol). The resulting solution was stirred at room temperature for 1 h.The reaction mixture was then diluted with ethyl acetate and washed withsaturated aqueous solutions of KH₂PO₄ and NaHCO₃, followed by brine. Theorganic layer was concentrated in vacuo and the residue was purified byreverse phase HPLC (acetonitrile-H₂O with 0.1% TFA as eluent) to give 26mg of the title compound (23% yield) as a white solid. MS: (ES) m/zfound 376.2.

Example 112: Synthesis of(S)-1-(4-chlorophenyl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide

a) To a mixture of 4-chloroaniline (2.56 g, 20 mmol) and con HCl (15 mL)in H₂O (30 mL) at −5° C. was added dropwisely a solution of NaNO₂ (1.38g, 20 mmol) in H₂O (5 mL) which was then stirred at 0° C. for 10 min toform the diazonium salt.

b) The above mixture was added slowly to a solution of ethylisocyanoacetate (2.26 g, 20 mmol) in MeOH (100 mL) and H₂O (10 mL) underice-bath. The mixture was allowed to slowly warm up to room temperatureover 5 h and solvent was evaporated. The residue was diluted with 10%MeOH in CH₂Cl₂ and washed with saturated aqueous solution of NaHCO₃,followed by brine. The organic layer was dried (Na₂SO₄), filtered andwas concentrated under reduced pressure to give the desired compound asa yellow solid (1.5 g, 29% yield, which was used directly for the nextstep). MS: (ES) m/z 252.2 (M+H⁺).

c) To a mixture of the above ester (1.5 g, 6 mmol), MeOH (30 mL), THF(50 mL) and DI H₂O (15 mL) was added LiOH monohydrate (2.5 g, 60 mmol).The resulting mixture was stirred at room temperature for 3 h. Themixture was diluted with ice-water, pH was adjusted to 3 with 1 N HCl,and the mixture was then extracted with 15% iPrOH in CH₂Cl₂. The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo to give thedesired compound as an off-white solid (900 mg, 83% yield, which wasused directly for the next step). MS: (ES) m/z 219.1 (M+H⁺).

d) To a suspension of the above 5-phenyl-1,2,4-oxadiazole-3-carboxylicacid (58 mg, 0.3 mmol),(S)-1-([1,2,4]triazolo[1,5-a]pyrazin-5-yl)pyrrolidin-3-aminehydrochloride salt (90 mg, 0.32 mmol) in DMF (5 mL) was addeddiethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31mmol). The resulting solution was stirred at room temperature for 1 h.The reaction mixture was diluted with ethyl acetate and washed withsaturated aqueous solutions of KH₂PO₄ and NaHCO₃, followed by brine. Theorganic layer was concentrated in vacuo and the residue purified byreverse phase HPLC (acetonitrile-H₂O with 0.1% TFA as eluent) to give 26mg of the title compound (23% yield) as white solid. MS: (ES) m/z found376.2.

Example 113: Synthesis of(S)-5-phenyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-1,2,4-oxadiazole-3-carboxamide

To a suspension of (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminehydrochloride salt (90 mg, 0.32 mmol) and5-phenyl-1,2,4-oxadiazole-3-carboxylic acid (58 mg, 0.3 mmol) in DMF (5mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU(120 mg, 0.31 mmol). The resulting solution was stirred at roomtemperature for 1 h. The reaction mixture was diluted with ethyl acetateand washed with saturated aqueous solutions of KH₂PO₄ and NaHCO₃,followed by brine. The organic layer was concentrated in vacuo and theresidue was purified by silica gel flash chromatography (2 to 5% MeOH inCH₂Cl₂ as eluent) followed by reverse phase HPLC (acetonitrile-H₂O with0.1% TFA as eluent) to give 15 mg of the title compound (18% yield) aswhite solid. MS: (ES) m/z found 374.1.

Example 114: Synthesis of(S)-1-phenyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-1H-1,2,4-triazole-3-carboxamide

To a suspension of (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-aminehydrochloride salt (60 mg, 0.21 mmol) and1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (40 mg, 0.21 mmol) in DMF(5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed byHATU (80 mg, 0.21 mmol). The resulting solution was stirred at roomtemperature for 1 h. The reaction mixture was then diluted with ethylacetate and washed with saturated aqueous solutions of KH₂PO₄ andNaHCO₃, followed by brine. The organic layer was concentrated in vacuoand the residue purified by reverse phase HPLC (acetonitrile-H₂O with0.1% TFA as eluent) to give 15 mg of the title compound (18% yield) aswhite solid. MS: (ES) m/z found 374.1

Example 115: Synthesis of 1-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylicacid (1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (41 mg, 0.20 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(55 mg, 0.20 mmol). To this was added triethylamine (0.112 mL, 0.80mmol) followed by HATU (84 mg, 0.22 mmol). The mixture was allowed tostir for 30 min, diluted with dichloromethane (1.0 mL), then washed withwater (3×1.0 mL), dried over sodium sulfate, filtered and concentrated.The crude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a white solid (9.5 mg, 0.02 mmol, 9%yield). ¹H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.87 (dd, J=4.8, 9.2 Hz,2H), 7.77 (d, J=2.6 Hz, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.56 (d, J=4.4 Hz,1H), 7.25 (t, J=9.2 Hz, 2H), 6.95 (d, J=2.5 Hz, 1H), 6.92 (dd, J=2.6,4.4 Hz, 1H), 6.84 (d, J=5.5 Hz, 1H), 4.95-3.65 (br, 5H), 2.58-2.30 (m,2H); MS: (ES) m/z calculated for C₂₁H₁₉FN₆O [M+H]⁺ 391.2, found 391.

Example 116: Synthesis of 2-phenyl-oxazole-4-carboxylic acid

2-Phenyl-oxazole-4-carboxylic acid ethyl ester (500 mg, 2.30 mmol) wasdissolved in a mixture of THF (2.3 mL) and MeOH (2.3 mL). To this wasadded NaOH (10% aqueous, 2.3 mL). The reaction mixture was stirred for 2h, and was then diluted with EtOAc and washed with 1N HCl The aqueouslayer was extracted with EtOAc and the combined organics were dried overNa₂SO₄, filtered and concentrated to give the product as a white solid(366 mg, 84%).

Example 117: Synthesis of 2-phenyl-oxazole-4-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-phenyl-oxazole-4-carboxylicacid (38 mg, 0.20 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(55 mg, 0.20 mmol). To this was added triethylamine (0.112 mL, 0.80mmol) followed by HATU (84 mg, 0.22 mmol). The mixture was allowed tostir for 30 min, and was then diluted with dichloromethane (1.0 mL),washed with water (3×1.0 mL), dried over sodium sulfate, filtered andconcentrated to give the crude material. The crude material was purifiedby reverse phase HPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). The combinedproduct fractions were lyophilized to give the TFA salt of the productas a white solid (27 mg, 0.06 mmol, 28% yield). ¹H NMR (400 MHz, CD3OD)δ 8.76 (d, J=6.6 Hz, 1H), 8.49 (s, 1H), 8.10-8.06 (m, 2H), 7.79 (dd,J=1.2, 2.4 Hz, 1H), 7.74 (d, J=5.5 Hz, 1H), 7.59-7.50 (m, 4H), 6.95 (dd,J=2.7, 4.2 Hz, 1H), 6.87 (d, J=5.4 Hz, 1H), 4.95-3.65 (br, 5H),2.60-2.30 (m, 2H); MS: (ES) m/z calculated for C₂₁H₁₉N₅O₂ [M+H]⁺ 374.2,found 374.

Example 118: Synthesis of 2-phenyl-thiazole-4-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-phenyl-thiazole-4-carboxylicacid (41 mg, 0.20 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(55 mg, 0.20 mmol). To this mixture was added triethylamine (0.112 mL,0.80 mmol) followed by HATU (84 mg, 0.22 mmol). The mixture was allowedto stir for 30 min and was then diluted with dichloromethane (1.0 mL)and washed with water (3×1.0 mL). The organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to give thecrude product. The crude product was purified by reverse phase HPLC(10:90-95:5 MeCN:H₂O+0.1% TFA). The combined product fractions werelyophilized to give the TFA salt of the product as a white solid (34 mg,0.07 mmol, 34% yield). ¹H NMR (400 MHz, CD3OD) δ 8.87 (d, J=6.7 Hz, 1H),8.26 (s, 1H), 8.07-8.01 (m, 2H), 7.79 (dd, J=1.2, 2.7 Hz, 1H), 7.74 (d,J=5.5 Hz, 1H), 7.59 (d, J=4.3 Hz, 1H), 7.51-7.46 (m, 3H), 6.95 (dd,J=2.3, 4.4 Hz, 1H), 6.87 (d, J=5.5 Hz, 1H), 4.95-3.65 (br, 5H),2.60-2.38 (m, 2H); MS: (ES) m/z calculated for C₂₁H₁₉N₅OS [M+H]⁺ 390.2,found 390.

Example 119: Synthesis of 1-o-tolyl-1H-pyrazole-3-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.4 mL) was added to a mixture of1-o-tolyl-1H-pyrazole-3-carboxylic acid (15 mg, 0.07 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(19 mg, 0.07 mmol). To this was added triethylamine (0.039 mL, 0.28mmol) followed by HATU (30 mg, 0.08 mmol). The mixture was allowed tostir for 30 min and was then diluted with dichloromethane (1.0 mL) andwashed with water (3×1.0 mL). The organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure to give thecrude product. The crude material was purified by reverse phase HPLC(10:90-95:5 MeCN:H₂O+0.1% TFA). The combined product fractions werelyophilized to give the TFA salt of the product as a white solid (12 mg,0.02 mmol, 34% yield). ¹H NMR (400 MHz, CD3OD) δ 8.62 (d, J=5.9 Hz, 1H),7.88 (d, J=2.5 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J=5.9 Hz, 1H), 7.54 (d,J=3.6 Hz, 1H), 7.40-7.25 (m, 4H), 6.94 (d, J=2.2 Hz, 1H), 6.91 (dd,J=2.6, 4.4 Hz, 1H), 6.82 (d, J=5.5 Hz, 1H), 4.95-3.65 (br, 5H),2.58-2.30 (m, 2H), 2.20 (s, 3H); MS: (ES) m/z calculated forC₂₂H₂₂N₆O[M+H]⁺ 387.2, found 387.

Example 120: Synthesis of 2-(4-fluoro-phenyl)-thiazole-4-carboxylic acid[1-(8-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of2-(4-fluoro-phenyl)-thiazole-4-carboxylic acid (31 mg, 0.14 mmol) and1-(8-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (40 mg, 0.14 mmol). To this mixture was addedtriethylamine (0.078 mL, 0.56 mmol) followed by HATU (57 mg, 0.15 mmol).The mixture was allowed to stir for 30 min and was then diluted withdichloromethane (1.0 mL) and washed with water (3×1.0 mL). The organicswere dried over sodium sulfate, filtered and concentrated under reducedpressure to give the crude product. The crude material was purified byreverse phase HPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). The combinedfractions were concentrated, taken up in CH₂Cl₂, washed with NaHCO₃,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting oil was then purified via flash chromatography on silica gel(CH₂Cl₂:MeOH gradient 99:1 to 90:10). The combined product fractionswere concentrated and then lyophilized from a mixture of MeCN and 1M HClto give the HCl salt of the product as a white solid (32 mg, 0.06 mmol,43% yield). ¹H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 8.09 (dd, J=5.1, 8.8Hz, 2H), 7.67 (d, J=5.5 Hz, 2H), 7.24 (t, J=8.8 Hz, 2H), 6.75 (d, J=5.5Hz, 2H), 4.85-4.75 (m, 1H), 4.30-4.22 (m, 1H), 4.10-3.90 (m, 3H), 2.64(s, 3H), 2.55-2.35 (m, 2H); MS: (ES) m/z calculated for C₂₂H₂₀FN₅OS[M+H]⁺ 422.2, found 422.

Example 121: Synthesis of 2-(4-fluorophenyl)-thiazole-4-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of2-(4-fluoro-phenyl)-thiazole-4-carboxylic acid (56 mg, 0.25 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(70 mg, 0.25 mmol). To this was added triethylamine (0.139 mL, 1.0 mmol)followed by HATU (106 mg, 0.28 mmol). The mixture was allowed to stirfor 30 min, diluted with dichloromethane (1.0 mL), then washed withwater (3×1.0 mL), dried over sodium sulfate, filtered and concentratedto give the crude product. The crude material was purified by reversephase HPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). The combined productfractions were lyophilized to give the TFA salt of the product as ayellow solid (67 mg, 0.13 mmol, 51% yield). ¹H NMR (400 MHz, CD3OD) δ8.85 (d, J=6.6 Hz, 1H), 8.23 (s, 1H), 8.09-8.05 (m, 2H), 7.76 (s, 1H),7.72 (d, J=5.9 Hz, 1H), 7.56 (s, 1H), 7.23 (t, J=8.8 Hz, 1H), 6.93 (dd,J=2.5, 4.4 Hz, 1H), 6.85 (d, J=5.9 Hz, 1H), 5.00-3.60 (m, 5H), 2.60-2.35(m, 2H); MS: (ES) m/z calculated for C₂₁H₁₈FN₅OS [M+H]⁺ 408.2, found408.

Example 122: Synthesis of1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid

a) A flask was charged with 4-hydroxytetrahydropyran (3.00 g, 29.4mmol), Methanesulfonyl chloride (2.39 mL, 30.9 mmol), triethylamine(8.20 mL, 58.8 mmol), and CH₂Cl₂. The resulting mixture was stirredovernight at room temperature. The reaction mixture was then washed withsaturated aqueous NaHCO₃ (100 mL) and water (100 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product thusobtained was used without further purification.

b) A vial was charged with ethyl-1H-pyrazole-3-carboxylate (3.74 g, 26.7mmol), the crude methanesulfonic acid tetrahydro-pyran-4-yl ester (29.4mmol), Cs₂CO₃ (17.4 g, 53.4 mmol), and DMF (100 mL). The reactionmixture was heated to 80° C. and stirred overnight. The reaction wasthen partitioned between CH₂Cl₂ (250 mL) and water (250 mL), and theorganic layer was washed with water (5×250 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude productcontaining 2 regioisomers was purified via flash chromatography onsilica gel (95:5-50:50 hexanes:EtOAc) and the later eluting isomer wasisolated. This was purified on silica gel a second time (85:15-60:40hexanes:EtOAc) to give the pure desired product (1.14 g, 19%).

c) 1-(Tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid ethyl ester(1.14 g, 5.09 mmol) was dissolved in a mixture of THF (5.0 mL) and MeOH(5.0 mL). To this was added NaOH (20% aqueous, 5.0 mL). The reactionmixture was stirred overnight and was then diluted with EtOAc and washedwith 1 M NaHSO₄. The aqueous layer was extracted with EtOAc and thecombined organics were dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the product as a white solid (802 mg,80%).

Example 123: Synthesis of1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-(tetrahydropyran-4-yl)-1H-pyrazole-3-carboxylic acid (31 mg, 0.16mmol) and 1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylaminedihydrochloride salt (45 mg, 0.16 mmol). To this was added triethylamine(0.089 mL, 0.64 mmol) followed by HATU (68 mg, 0.18 mmol). The mixturewas allowed to stir for 30 min, and was then diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a pale yellow solid (29 mg, 0.06mmol, 37% yield). ¹H NMR (400 MHz, CD3OD) δ 8.48 (d, J=6.2 Hz, 1H),7.78-7.70 (m, 3H), 7.55 (s, 1H), 6.91 (dd, J=2.5, 4.4 Hz, 1H), 6.83 (d,J=5.5 Hz, 1H), 6.73 (d, J=2.2 Hz, 1H), 5.00-3.60 (m, 8H), 3.55 (dt,J=2.2, 11.7 Hz, 2H), 2.60-2.39 (m, 2H), 2.20-1.95 (m, 4H); MS: (ES) m/zcalculated for C₂₀H₂₄N₆O₂ [M+H]⁺ 381.2, found 381.

Example 124: Synthesis of1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid(1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-(tetrahydropyran-4-yl)-1H-pyrazole-3-carboxylic acid (35 mg, 0.18mmol) and 1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-ylamine (50mg, 0.18 mmol). To this was added triethylamine (0.100 mL, 0.72 mmol)followed by HATU (76 mg, 0.20 mmol). The mixture was allowed to stir for30 min and was then diluted with dichloromethane (1.0 mL), washed withwater (3×1.0 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude was purified by reverse phase HPLC(10:90-95:5 MeCN:H₂O+0.1% TFA). The combined product fractions werelyophilized to give the TFA salt of the product as a white solid (16 mg,0.03 mmol, 18% yield). ¹H NMR (400 MHz, CD3OD) δ 9.25 (s, 1H), 7.85 (d,J=5.1 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.20 (d, J=5.5 Hz, 1H), 6.73 (d,J=2.5 Hz, 1H), 5.00-3.60 (m, 8H), 3.55 (dt, J=2.2, 11.7 Hz, 2H),2.60-2.39 (m, 2H), 2.20-1.95 (m, 4H); MS: (ES) m/z calculated forC₁₈H₂₂N₈O₂ [M+H]⁺ 383.2, found 383.

Example 125: Synthesis of1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid(1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-(tetrahydro-pyran-4-yl)-1H-pyrazole-3-carboxylic acid (35 mg, 0.18mmol) and 1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-ylaminedihydrochloride salt (50 mg, 0.18 mmol). To this was added triethylamine(0.100 mL, 0.72 mmol) followed by HATU (76 mg, 0.20 mmol). The mixturewas allowed to stir for 30 min and was then diluted with dichloromethane(1.0 mL), washed with water (3×1.0 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas purified by reverse phase HPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). Thecombined product fractions were lyophilized to give the TFA salt of theproduct as a pale yellow oil (35 mg, 0.07 mmol, 39% yield). ¹H NMR (400MHz, CD3OD) δ 8.02 (s, 1H), 7.90 (d, J=5.9 Hz, 1H), 7.79 (s, 1H), 7.73(d, J=2.5 Hz, 1H), 7.14 (d, J=5.5 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H),5.00-3.70 (m, 8H), 3.55 (dt, J=2.2, 11.7 Hz, 2H), 2.60-2.30 (m, 2H),2.20-1.95 (m, 4H); MS: (ES) m/z calculated for C₁₉H₂₃N₇O₂ [M+H]⁺ 382.2,found 382.

Example 126: Synthesis of 2-o-tolyloxazole-4-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

a) A flask was charged with ethyl 2-chlorooxazole-4-carboxylate (500 mg,2.85 mmol), 2-methylbenzeneboronic acid (387 mg, 2.85 mmol), Pd(PPh₃)₄(132 mg, 0.114 mmol), K₂CO₃ (787 mg, 5.7 mmol), and toluene (29 mL). Thereaction mixture was degassed under a stream of N₂, and was then heatedto 90° C. for 1 h. The reaction was then diluted with EtOAc and washedwith 1M aqueous NaOH. The organic layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The crude material was purifiedon via flash chromatography on silica gel (hexanes:EtOAc) to give a 2:1mixture of product to ethyl 2-chlorooxazole-4-carboxylate (360 mg) thatwas carried on without further purification.

b) The 2:1 mixture of 2-o-Tolyl-oxazole-4-carboxylic acid ethylester:ethyl 2-chlorooxazole-4-carboxylate (360 mg) was dissolved in amixture of THF (1.0 mL) and MeOH (1.0 mL). To this was added NaOH (20%aqueous, 1.0 mL). The reaction mixture was stirred overnight and wasthen diluted with EtOAc (50 mL) and washed with 1M NaHSO₄ (50 mL). Theaqueous layer was extracted with EtOAc (2×50 mL) and the combinedorganics were dried over Na₂SO₄, filtered and concentrated to give a 2:1mixture of product: 2-Chloro-oxazole-4-carboxylic acid (360 mg).

c) The 2:1 mixture of acids from step b (37 mg) was dissolved in DMSO(0.5 mL) and 1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylaminedihydrochloride salt (50 mg, 0.18 mmol) was added. To this was addedtriethylamine (0.100 mL, 0.72 mmol) followed by HATU (76 mg, 0.20 mmol).The mixture was allowed to stir for 30 min and was then diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure to givethe crude. The crude was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a yellow solid (26 mg, 0.05 mmol,29% yield). ¹H NMR (400 MHz, CD3OD) δ 8.61 (d, J=6.2 Hz, 1H), 8.49 (s,1H), 7.94 (d, J=7.7 Hz, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.71 (d, J=5.4 Hz,1H), 7.56 (d, J=2.9 Hz, 1H), 7.40-7.26 (m, 3H), 6.92 (dt, J=1.8, 2.6 Hz,1H), 6.83 (d, J=5.5 Hz, 1H), 5.00-3.60 (m, 5H), 2.66 (s, 3H), 2.60-2.38(m, 2H); MS: (ES) m/z calculated for C₂₂H₂₁N₅O₂ [M+H]⁺388.2, found 388.

Example 127: Synthesis of 2-phenyloxazole-4-carboxylic acid(1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-phenyloxazole-4-carboxylicacid (42 mg, 0.22 mmol) and1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-ylamine dihydrochloride salt(60 mg, 0.22 mmol). To this was added triethylamine (0.123 mL, 0.88mmol) followed by HATU (91 mg, 0.24 mmol). The mixture was allowed tostir for 30 min and was then diluted with dichloromethane (1.0 mL),washed with water (3×1.0 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude material was purified byreverse phase HPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). The combined productfractions were lyophilized to give the TFA salt of the product as awhite solid (62 mg, 0.13 mmol, 58% yield). ¹H NMR (400 MHz, CD3OD) δ8.71 (d, J=6.3 Hz, 1H), 8.46 (s, 1H), 8.06-8.02 (m, 3H), 7.91 (d, J=5.5Hz, 1H), 7.80 (s, 1H), 7.49 (m, 3H), 7.15 (d, J=5.9 Hz, 1H), 5.00-3.80(m, 5H), 2.60-2.38 (m, 2H); MS: (ES) m/z calculated for C₂₀H₁₈N₆O₂[M+H]⁺375.2, found 375.

Example 128: Synthesis of 2-phenyloxazole-4-carboxylic acid(1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-phenyloxazole-4-carboxylicacid (42 mg, 0.22 mmol) and1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-ylamine (60 mg, 0.22mmol). To this was added triethylamine (0.123 mL, 0.88 mmol) followed byHATU (91 mg, 0.24 mmol). The mixture was allowed to stir for 30 min andwas then diluted with dichloromethane (1.0 mL), washed with water (3×1.0mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude material was purified by reverse phase HPLC(10:90-95:5 MeCN:H₂O+0.1% TFA). The combined product fractions werelyophilized to give the TFA salt of the product as a white solid (58 mg,0.12 mmol, 54% yield). ¹H NMR (400 MHz, CD3OD) δ 9.26 (s, 1H), 8.70 (d,J=5.9 Hz, 0.5H), 8.45 (s, 1H), 8.04 (d, J=5.5 Hz, 2H), 7.86 (d, J=5.5Hz, 1H), 7.49 (m, 3H), 7.21 (d, J=5.5 Hz, 1H), 5.00-3.80 (m, 5H),2.60-2.38 (m, 2H); MS: (ES) m/z calculated for C₁₉H₁₇N₇O₂ [M+H]⁺ 376.2,found 376.

Example 129: Synthesis of 2-phenylthiazole-4-carboxylic acid(1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-phenylthiazole-4-carboxylicacid (45 mg, 0.22 mmol) and1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-ylamine dihydrochloride salt(60 mg, 0.22 mmol). To this was added triethylamine (0.123 mL, 0.88mmol) followed by HATU (91 mg, 0.24 mmol). The mixture was allowed tostir for 30 min and was then diluted with dichloromethane (1.0 mL),washed with water (3×1.0 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude material was purified byreverse phase chromatography (10:90-95:5 MeCN:H₂O+0.1% TFA). Thecombined product fractions were lyophilized to give the TFA salt of theproduct as a pale yellow solid (74 mg, 0.15 mmol, 67% yield). ¹H NMR(400 MHz, CD3OD) δ 8.82 (d, J=6.3 Hz, 1H), 8.23 (s, 1H), 8.03-8.01 (m,3H), 7.92-7.90 (m, 1H), 7.88 (s, 1H), 7.48-7.45 (m, 3H), 7.15 (d, J=5.8Hz, 1H), 4.98-3.80 (m, 5H), 2.60-2.40 (m, 2H); MS: (ES) m/z calculatedfor C₂₀H₁₈N₆OS [M+H]⁺ 391.2, found 391.

Example 130: Synthesis of 2-phenylthiazole-4-carboxylic acid(1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-phenylthiazole-4-carboxylicacid (45 mg, 0.22 mmol) and1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-ylaminedihydrochloride salt (60 mg, 0.22 mmol). To this was added triethylamine(0.123 mL, 0.88 mmol) followed by HATU (91 mg, 0.24 mmol). The mixturewas allowed to stir for 30 min and was then diluted withdichloromethane, washed with water (3×), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas triturated with MeCN, filtered, and the solid was washed with MeCN.The resulting solid was taken up in MeCN and 1 M HCl, then lyophilizedto give the HCl salt of the product as a white solid (17 mg, 0.04 mmol,18% yield). ¹H NMR (400 MHz, CD3OD) δ 9.31 (s, 1H), 8.85 (d, J=3.6 Hz,1H), 8.24 (s, 1H), 8.02 (d, J=3.6 Hz, 2H), 7.92 (d, J=5.4 Hz, 1H), 7.47(s, 3H), 7.19 (d, J=5.4 Hz, 1H), 5.00-3.80 (m, 5H), 2.60-2.40 (m, 2H);MS: (ES) m/z calculated for C₁₉H₁₇N₇O S [M+H]⁺ 392.2, found 392.

Example 131: Synthesis of 1-o-tolyl-1H-pyrazole-3-carboxylic acid

a) A flask was charged with 2-iodotoluene (0.964 mL, 7.57 mmol),ethyl-1H-pyrazole-3-carboxylate (1.00 g, 7.14 mmol), CuI (272 mg, 1.43mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.451 mL, 2.86 mmol),and K₂CO₃ (3.15 g, 22.8 mmol). The reaction mixture was then heated to140° C. for 3 h. The reaction was then partitioned between CH₂Cl₂ andsaturated aqueous NH₄Cl and separated. The organic layer was washed withwater, dried over Na₂SO₄, filtered and concentrated. The crude waspurified via flash chromatography on silica gel (90:10-70:30hexanes:methyl tert-butyl ether) to give the product (238 mg, 1.03 mmol,14%) as a colorless oil.

b) 1-o-Tolyl-1H-pyrazole-3-carboxylic acid ethyl ester (238 mg, 1.03mmol) was dissolved in a mixture of THF (2.0 mL) and MeOH (2.0 mL). Tothis was added NaOH (20% aqueous, 1.0 mL). The reaction mixture wasstirred for 2 h, and was then diluted with EtOAc and washed with 1M HCl.The aqueous layer was extracted with EtOAc and the combined organicswere dried over Na₂SO₄, filtered and concentrated to give the product asa white solid (164 mg, 0.81 mmol, 79%).

Example 132: Synthesis of 1-o-tolyl-1H-pyrazole-3-carboxylic acid(1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-o-tolyl-1H-pyrazole-3-carboxylic acid (44 mg, 0.22 mmol) and1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-ylamine dihydrochloride salt(60 mg, 0.22 mmol). To this was added triethylamine (0.123 mL, 0.88mmol) followed by HATU (91 mg, 0.24 mmol). The mixture was allowed tostir for 30 min and was then diluted with dichloromethane (1.0 mL),washed with water (3×1.0 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified byreverse phase chromatography (10:90-95:5 MeCN:H₂O+0.1% TFA). Thecombined product fractions were lyophilized to give the TFA salt of theproduct as a yellow solid (29 mg, 0.06 mmol, 26% yield). ¹H NMR (400MHz, CD3OD) δ 8.58 (d, J=7.3 Hz, 1H), 8.01 (d, J=0.7 Hz, 1H), 7.92-7.87(m, 2H), 7.78 (d, J=1.1 Hz, 1H), 7.40-7.28 (m, 4H), 7.12 (d, J=5.8 Hz,1H), 6.93 (d, J=2.2 Hz, 1H), 4.94-3.80 (m, 5H), 2.56-2.32 (m, 2H), 2.20(s, 3H); MS: (ES) m/z calculated for C₂₁H₂₁N₇O [M+H]⁺ 388.2, found 388.

Example 133: Synthesis of 1-o-tolyl-1H-pyrazole-3-carboxylic acid(1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-o-tolyl-1H-pyrazole-3-carboxylic acid (44 mg, 0.22 mmol) and1-[1,2,4]triazolo[4,3-a]pyrazin-8-yl-pyrrolidin-3-ylaminedihydrochloride salt (60 mg, 0.22 mmol). To this was added triethylamine(0.123 mL, 0.88 mmol) followed by HATU (91 mg, 0.24 mmol). The mixturewas allowed to stir for 30 min and was then diluted withdichloromethane, washed with water (3×), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas triturated with MeCN, filtered, and the solid was washed with MeCN.The resulting solid was taken up in MeCN and 1M HCl and lyophilized togive the HCl salt of the product as a white solid (13 mg, 0.03 mmol, 12%yield). ¹H NMR (400 MHz, CD3OD) δ 9.30 (s, 1H), 7.91 (d, J=5.8 Hz, 1H),7.88 (s, 1H), 7.40-7.28 (m, 4H), 7.17 (m, 1H), 6.95 (s, 1H), 4.94-4.70(m, 4H), 4.24-3.84 (m, 3H), 2.62-2.38 (m, 2H), 2.20 (s, 3H); MS: (ES)m/z calculated for C₂₀H₂₀N₈O [M+H]⁺ 389.2, found 389.

Example 134: Synthesis of 2-o-tolyl-thiazole-4-carboxylic acid

a) A flask was charged 2-methylbenzeneboronic acid (500 mg, 3.68 mmol),ethyl 2-bromothiazole-4-carboxylate (869 mg, 3.68 mmol), Pd(PPh₃)₄ (173mg, 0.150 mmol), K₂CO₃ (2 M aqueous, 3.68 mL, 7.36 mmol), and toluene(37 mL). The reaction mixture was degassed under a stream of N₂, thenheated to 90° C. and stirred overnight. The reaction was then dilutedwith EtOAc and washed with 1M aqueous NaOH. The aqueous layer wasextracted with EtOAc (2×100 mL), and the combined organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude was purified via flash chromatography on silica gel(95:5-70:30 hexanes:EtOAc) to give the product (550 mg, 2.22 mmol, 60%)as a pale yellow oil.

b) 2-o-Tolyl-thiazole-4-carboxylic acid ethyl ester (550 mg, 2.22 mmol)was dissolved in a mixture of THF (1.0 mL) and MeOH (1.0 mL). To thiswas added NaOH (20% aqueous, 0.444 mL). The reaction mixture was stirredovernight and was then diluted with CH₂Cl₂ (30 mL) and washed with 1MNaHSO₄ (30 mL). The aqueous layer was extracted with CH₂Cl₂ (2×30 mL),then the combined organic layers were washed with water (1×30 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe product (434 mg, 1.98 mmol, 89%) as a white solid.

Example 135: Synthesis of 2-o-tolylthiazole-4-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-o-tolylthiazole-4-carboxylicacid (48 mg, 0.22 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(60 mg, 0.22 mmol). To this was added triethylamine (0.123 mL, 0.88mmol) followed by HATU (91 mg, 0.24 mmol). The mixture was allowed tostir for 30 min, diluted with dichloromethane (1.0 mL), then washed withwater (3×1.0 mL), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude material was purified by reverse phaseHPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). The combined product fractions werelyophilized to give the TFA salt of the product as a yellow solid (10mg, 0.02 mmol, 9% yield). ¹H NMR (400 MHz, CD3OD) δ 8.74 (d, J=6.7 Hz,1H), 8.34 (s, 1H), 7.78 (dd, J=1.2, 2.7 Hz, 1H), 7.76-7.70 (m, 2H), 7.57(d, J=4.3 Hz, 1H), 7.42-7.26 (m, 3H), 6.93 (dd, J=2.8, 4.7 Hz, 1H), 6.84(d, J=5.9 Hz, 1H), 5.00-4.80 (m, 1H), 4.60-3.60 (br, 4H), 2.60-2.36 (m,2H), 2.55 (s, 3H); MS: (ES) m/z calculated for C₂₂H₂₁N₅OS [M+H]⁺ 404.2,found 404.

Example 136: Synthesis of 2-o-tolylthiazole-4-carboxylic acid(1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 2-o-tolylthiazole-4-carboxylicacid (48 mg, 0.22 mmol) and1-imidazo[1,2-a]pyrazin-8-yl-pyrrolidin-3-ylamine dihydrochloride salt(60 mg, 0.22 mmol). To this was added triethylamine (0.123 mL, 0.88mmol) followed by HATU (91 mg, 0.24 mmol). The mixture was allowed tostir for 30 min after which time it was diluted with dichloromethane(1.0 mL), washed with water (3×1.0 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude productcontaining material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a yellow solid (58 mg, 0.11 mmol,51% yield). ¹H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.04 (d, J=1.2 Hz,1H), 7.92 (d, J=5.5 Hz, 1H), 7.81 (d, J=1.2 Hz, 1H), 7.73 (dd, J=1.5,7.8 Hz, 1H), 7.42-7.26 (m, 3H), 7.16 (d, J=5.5 Hz, 1H), 5.00-4.80 (m,1H), 4.60-3.60 (br, 4H), 2.60-2.38 (m, 2H), 2.55 (s, 3H); MS: (ES) m/zcalculated for C₂₁H₂₀N₆OS [M+H]⁺405.2, found 405.

Example 137: Synthesis of1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt

a) A solution of chloroacetone (2.81 mL, 35.3 mmol) in acetone (50 mL)was added dropwise to a slurry of 2-(trichloroacetyl)pyrrole (5.00 g,23.5 mmol), acetone (70 mL) and K₂CO₃ (9.74 g, 70.5 mmol). The mixturewas stirred overnight at room temperature. The reaction mixture was thenfiltered and the solids were washed with acetone. The filtrate wasconcentrated and the residue was partitioned between water (100 mL) andethyl acetate (100 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (100 mL). The combined organic layerswere washed with water (3×100 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified viaflash chromatography on silica gel using hexanes:ethyl acetate to givethe product (2.35 g, 15.8 mmol, 67%).

b) A mixture of 3-methyl-pyrrolo[2,1-c][1,4]oxazin-1-one (2.35 g, 15.8mmol), NH₄OAc (5.32 g, 69.0 mmol) and AcOH (13.8 mL) was heated to 160°C. in a sealed vial for 48 h. The solvent was removed in vacuo, and thecrude was taken up in CH₂Cl₂. This was washed with saturated NaHCO₃,dried over Na₂SO₄, filtered and concentrated under reduced pressure.Purification via flash chromatography (silica gel using hexanes:EtOAc)gave the product (710 mg, 4.79 mmol, 35%).

c) POCl₃ (2 mL) was added to 3-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one(710 mg, 4.79 mmol) and the solution was heated to 105° C. for 3 h. Thereaction mixture was concentrated in vacuo. The resulting oil was takenup in CH₂Cl₂ and washed with saturated aqueous NaHCO₃ then water. Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification via flash chromatography on silica gel(95:5-70:30 hexanes:EtOAc) gave the product (798 mg, 4.79 mmol,quantitative yield) as a yellow solid.

d) A vial was charged with 1-chloro-3-methylpyrrolo[1,2-a]pyrazine (798mg, 4.79 mmol), (S)-3-(Boc-amino)pyrrolidine (901 mg, 4.84 mmol),iPr₂NEt (2.52 mL, 14.52 mmol), and 1-butyl-3-methyl-1H-imidazoliumtetrafluoroborate (catalytic) and heated to 110° C. for 15 h. Thereaction mixture was concentrated in vacuo and purified via flashchromatography on silica gel (99:1-90:10 CH₂Cl₂:MeOH) to give theproduct (965 mg, 3.05 mmol, 64%).

e) HCl (4 M in dioxane, 3.80 mL, 15.2 mmol) was added to[1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester (965 mg, 3.04 mmol) in MeOH (10 mL). This was stirredovernight then concentrated to give the product (860 mg, 2.97 mmol, 98%)as a white solid.

Example 138: Synthesis of 1-(4-fluorophenyl)-1H-pyrazole-3-carboxylicacid [1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of1-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (50 mg, 0.24 mmol) and1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (69 mg, 0.29 mmol). To this was added triethylamine(0.134 mL, 0.96 mmol) followed by HATU (99 mg, 0.26 mmol). The mixturewas allowed to stir for 30 min, and was then diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a white solid (31 mg, 0.06 mmol, 25%yield). ¹H NMR (400 MHz, CD3OD) δ 8.75 (d, J=7.0 Hz, 1H), 8.28 (d, J=2.7Hz, 1H), 7.88 (m, 2H), 7.68 (q, J=1.2 Hz, 1H), 7.52 (d, J=4.3 Hz, 1H),7.49 (s, 1H), 7.27-7.22 (m, 2H), 6.96 (d, J=2.4 Hz, 1H), 6.87 (dd,J=2.7, 4.3 Hz, 1H), 5.00-4.80 (m, 1H), 4.60-3.60 (br, 4H), 2.60-2.38 (m,2H), 2.30 (d, J=1.1 Hz, 3H); MS: (ES) m/z calculated for C₂₂H₂₁FN₆O[M+H]⁺ 405.2, found 405.

Example 139: Synthesis of 1-phenyl-1H-[1,2,4]triazole-3-carboxylic acid[1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (50 mg, 0.26 mmol) and1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (74 mg, 0.26 mmol). To this was added triethylamine(0.145 mL, 1.04 mmol) followed by HATU (110 mg, 0.29 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a brown solid (66 mg, 0.13 mmol, 51%yield). ¹H NMR (400 MHz, CD3OD) δ 9.14 (s, 1H), 7.88 (td, J=1.2, 6.2 Hz,2H), 7.68 (q, J=1.2 Hz, 1H), 7.62-7.44 (m, 6H), 6.88 (dd, J=2.3, 4.3 Hz,1H), 5.00-4.80 (m, 1H), 4.60-3.60 (br, 4H), 2.60-2.38 (m, 2H), 2.30 (d,J=1.1 Hz, 3H); MS: (ES) m/z calculated for C₂₁H₂₁N₇O [M+H]⁺ 388.2, found388.

Example 140: Synthesis of 1-phenyl-1H-imidazole-4-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-phenyl-1H-imidazole-4-carboxylic acid (34 mg, 0.18 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(50 mg, 0.18 mmol). To this was added triethylamine (0.100 mL, 0.72mmol) followed by HATU (76 mg, 0.20 mmol). The mixture was allowed tostir for 30 min after which time it was diluted with dichloromethane(1.0 mL), washed with water (3×1.0 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas purified by reverse phase HPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). Thecombined product fractions were lyophilized to give the TFA salt of theproduct as a pale yellow solid (49 mg, 0.10 mmol, 56% yield). ¹H NMR(400 MHz, CD3OD) δ 8.23 (d, J=1.1 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.79(dd, J=1.2, 2.8 Hz, 1H), 7.73 (d, J=5.5 Hz, 1H), 7.64-7.52 (m, 5H),7.50-7.42 (m, 1H), 6.94 (dd, J=2.3, 4.3 Hz, 1H), 6.86 (d, J=5.5 Hz, 1H),5.00-4.80 (m, 1H), 4.50-3.50 (br, 4H), 2.58-2.48 (m, 1H), 2.48-2.35 (br,1H); MS: (ES) m/z calculated for C₂₁H₂₀N₆O [M+H]⁺ 373.2, found 373.

Example 141: Synthesis of2-(4-hydroxypiperidin-1-yl)-thiazole-4-carboxylic acid[1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of2-(4-hydroxypiperidin-1-yl)-thiazole-4-carboxylic acid (48 mg, 0.21mmol) and 1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (60 mg, 0.21 mmol). To this was added triethylamine(0.117 mL, 0.84 mmol) followed by HATU (87 mg, 0.23 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined fractions were concentrated, taken upin CH₂Cl₂, washed with NaHCO₃, dried over Na₂SO₄, filtered andconcentrated. The resulting oil was then purified via flashchromatography on silica gel (CH₂Cl₂:MeOH gradient 99:1 to 90:10). Thecombined product fractions were concentrated and then lyophilized from amixture of MeCN and 1 M HCl to give the HCl salt of the product as ayellow solid (22 mg, 0.04 mmol, 19% yield). ¹H NMR (400 MHz, CD3OD) δ7.37 (s, 1H), 7.28 (q, J=1.2 Hz, 1H), 7.25 (s, 1H), 6.86 (d, J=4.3 Hz,1H), 6.57 (dd, J=2.7, 4.3 Hz, 1H), 5.48 (s, 2H), 4.70-4.60 (m, 1H),4.22-3.78 (m, 8H), 3.28-3.10 (m, 1H), 2.40-2.28 (m, 1H), 2.22-2.12 (m,4H), 1.96-1.88 (m, 2H); 1.62-1.52 (m, 2H); MS: (ES) m/z calculated forC₂₁H₂₆N₆O₂S [M+H]⁺ 427.2, found 427.

Example 142: Synthesis of 1-phenyl-1H-imidazole-4-carboxylic acid[1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of1-phenyl-1H-imidazole-4-carboxylic acid (32 mg, 0.17 mmol) and1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (50 mg, 0.17 mmol). To this was added triethylamine(0.095 mL, 0.68 mmol) followed by HATU (72 mg, 0.19 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a light brown solid (33 mg, 0.07mmol, 39% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J=1.6 Hz, 1H), 8.15(d, J=1.6 Hz, 1H), 7.67 (q, J=1.2 Hz, 1H), 7.62-7.45 (m, 6H), 6.88 (q,J=2.3 Hz, 1H), 5.00-4.80 (m, 1H), 4.60-3.60 (br, 4H), 2.58-2.48 (m, 1H),2.48-2.38 (br, 1H), 2.30 (d, J=1.1 Hz, 3H); MS: (ES) m/z calculated forC₂₂H₂₂N₆O [M+H]⁺ 387.2, found 387.

Example 143: Synthesis of 1-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid [1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of1-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid (38 mg, 0.17 mmol) and1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (50 mg, 0.17 mmol). To this was added triethylamine(0.095 mL, 0.68 mmol) followed by HATU (72 mg, 0.19 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a white solid (50 mg, 0.09 mmol, 55%yield). ¹H NMR (400 MHz, CD3OD) δ 8.78 (d, J=7.0 Hz, 0.5H), 8.33 (d,J=2.7 Hz, 1H), 7.87 (td, J=2.4, 9.0 Hz, 2H), 7.67 (q, J=1.2 Hz, 1H),7.51 (td, J=3.1, 9.0 Hz, 4H), 6.98 (d, J=2.8 Hz, 1H), 6.87 (q, J=2.8,1.9 Hz, 1H), 4.50-3.50 (br, 5H), 2.58-2.48 (m, 1H), 2.48-2.38 (br, 1H),2.30 (d, J=0.7 Hz, 3H); MS: (ES) m/z calculated for C₂₂H₂₁ClN₆O [M+H]⁺421.2, found 421.

Example 144: Synthesis of 2-pyrrolidin-1-yl-thiazole-4-carboxylic acid[1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of2-pyrrolidin-1-yl-thiazole-4-carboxylic acid (34 mg, 0.17 mmol) and1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (50 mg, 0.17 mmol). To this was added triethylamine(0.095 mL, 0.68 mmol) followed by HATU (72 mg, 0.19 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a reddish solid (20 mg, 0.04 mmol,23% yield). ¹H NMR (400 MHz, CD3OD) δ 7.67 (dd, J=1.2, 2.3 Hz, 1H), 7.52(d, J=4.6 Hz, 1H), 7.49 (s, 1H), 7.36 (s, 1H), 6.87 (dd, J=2.7, 4.7 Hz,1H), 5.00-4.80 (m, 1H), 4.50-3.50 (br, 4H), 3.50-3.40 (m, 3H), 2.58-2.48(m, 1H), 2.48-2.38 (br, 1H), 2.30 (d, J=0.7 Hz, 3H), 2.10-2.00 (m, 4H);MS: (ES) m/z calculated for C₂₀H₂₄N₆OS [M+H]⁺ 397.2, found 397.

Example 145: Synthesis of 2-phenyloxazole-4-carboxylic acid[1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of 2-phenyloxazole-4-carboxylicacid (32 mg, 0.17 mmol) and1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (50 mg, 0.17 mmol). To this was added triethylamine(0.095 mL, 0.68 mmol) followed by HATU (72 mg, 0.19 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a light brown solid (42 mg, 0.08mmol, 49% yield). ¹H NMR (400 MHz, CD3OD) d 8.74 (d, J=6.7 Hz, 1H), 8.49(s, 1H), 8.10-8.06 (m, 2H), 7.68 (dd, J=1.2, 2.7 Hz, 1H), 7.57-7.50 (m,4H), 6.88 (dd, J=2.7, 4.7 Hz, 1H), 5.00-4.80 (m, 1H), 4.50-3.50 (br,4H), 2.58-2.48 (m, 1H), 2.48-2.38 (br, 1H), 2.31 (d, J=1.1 Hz, 3H); MS:(ES) m/z calculated for C₂₂H₂₁N₅O₂ [M+H]⁺ 388.2, found 388.

Example 146: Synthesis of 2-phenylthiazole-4-carboxylic acid[1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of 2-phenylthiazole-4-carboxylicacid (43 mg, 0.21 mmol) and1-(3-methylpyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (60 mg, 0.21 mmol). To this was added triethylamine(0.117 mL, 0.84 mmol) followed by HATU (87 mg, 0.23 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a gray solid (30 mg, 0.06 mmol, 28%yield). ¹H NMR (400 MHz, CD3OD) δ 8.87 (d, J=6.6 Hz, 1H), 8.26 (s, 1H),8.06-8.03 (m, 2H), 7.68 (dd, J=1.2, 2.7 Hz, 1H), 7.54-7.45 (m, 5H), 6.88(dd, J=2.4, 6.7 Hz, 1H), 5.00-4.80 (m, 1H), 4.50-3.50 (br, 4H),2.60-2.40 (m, 2H), 2.31 (d, J=1.1 Hz, 3H); MS: (ES) m/z calculated forC₂₂H₂₁N₅OS [M+H]⁺ 404.2, found 404.

Example 147: Synthesis of1-(4-fluorophenyl)-1H-[1,2,4]triazole-3-carboxylic acid[1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-yl]-amide

DMSO (0.5 mL) was added to a mixture of1-(4-fluorophenyl)-1H-[1,2,4]triazole-3-carboxylic acid and1-(3-methyl-pyrrolo[1,2-a]pyrazin-1-yl)-pyrrolidin-3-ylaminedihydrochloride salt (60 mg, 0.21 mmol). To this was added triethylamine(0.150 mL, 1.05 mmol) followed by HATU (87 mg, 0.23 mmol). The mixturewas allowed to stir for 30 min after which time it was diluted withdichloromethane (1.0 mL), washed with water (3×1.0 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified by reverse phase HPLC (10:90-95:5MeCN:H₂O+0.1% TFA). The combined product fractions were lyophilized togive the TFA salt of the product as a yellow solid (11 mg, 0.02 mmol,10% yield). ¹H NMR (400 MHz, CD3OD) δ 9.10 (s, 1H), 9.07 (d, J=6.2 Hz,1H), 7.92-7.88 (m, 2H), 7.68 (dd, J=1.2, 2.6 Hz, 1H), 7.53 (d, J=4.4 Hz,1H), 7.50 (s, 1H), 7.34 (t, J=8.6 Hz, 2H), 6.89 (dd, J=2.4, 4.4 Hz, 1H),5.00-4.80 (m, 1H), 4.50-3.50 (br, 4H), 2.60-2.40 (m, 2H), 2.31 (d, J=1.1Hz, 3H); MS: (ES) m/z calculated for C₂₁H₂₀FN₇O [M+H]⁺ 406.2, found 406.

Example 148: Synthesis of 6-methylquinazoline-2-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of 6-methylquinazoline-2-carboxylicacid.HCl (27 mg, 0.12 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(33 mg, 0.12 mmol). To this was added triethylamine (0.084 mL, 0.60mmol) followed by HATU (49 mg, 0.13 mmol). The mixture was allowed tostir for 30 min after which time it was diluted with dichloromethane(1.0 mL), washed with water (3×1.0 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas purified by reverse phase chromatography (10:90-95:5 MeCN:H₂O+0.1%TFA). The combined product fractions were lyophilized to give the TFAsalt of the product as a reddish solid (13 mg, 0.03 mmol, 22% yield). ¹HNMR (400 MHz, CD3OD) δ 9.55 (s, 1H), 8.11 (d, J=9.4 Hz, 1H), 7.98 (d,J=9.4 Hz, 2H), 7.53 (dd, J=1.2, 2.4 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H),7.50 (s, 1H), 6.89 (dd, J=2.3, 4.8 Hz, 1H), 5.00-4.80 (m, 1H), 4.50-3.50(br, 4H), 2.63 (s, 3H), 2.60-2.40 (m, 2H), 2.31 (d, J=1.1 Hz, 3H); MS:(ES) m/z calculated for C₂₂H₂₂N₆O [M+H]⁺ 387.2, found 387.

Example 149: Synthesis of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid(1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-yl)-amide

DMSO (0.5 mL) was added to a mixture of1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid (42 mg, 0.22 mmol) and1-pyrrolo[1,2-a]pyrazin-1-yl-pyrrolidin-3-ylamine dihydrochloride salt(60 mg, 0.22 mmol). To this was added triethylamine (0.123 mL, 0.88mmol) followed by HATU (91 mg, 0.24 mmol). The mixture was allowed tostir for 30 min after which time it was diluted with dichloromethane(1.0 mL), washed with water (3×1.0 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas purified by reverse phase HPLC (10:90-95:5 MeCN:H₂O+0.1% TFA). Thecombined product fractions were lyophilized to give the TFA salt of theproduct as a pale yellow solid (68 mg, 0.14 mmol, 63% yield). ¹H NMR(400 MHz, CD3OD) δ 9.03 (d, J=6.7 Hz, 1H), 8.97 (s, 1H), 7.89 (d, J=8.2Hz, 2H), 7.79 (dd, J=1.2, 2.7 Hz, 1H), 7.74 (d, J=5.9 Hz, 1H), 7.65-7.50(m, 4H), 6.95 (dd, J=2.8, 4.7 Hz, 1H), 6.87 (d, J=5.9 Hz, 1H), 5.00-4.80(m, 1H), 4.70-3.70 (br, 4H), 2.60-2.38 (m, 2H); MS: (ES) m/z calculatedfor C₂₀H₁₉N₇O [M+H]⁺ 374.2, found 374.

Example 150

The compounds in the Table below were prepared as described above.Characterization data (NMR) is provided for each.

TABLE 1 Specific Examples Avg Avg Bind Ser IC50 IC50 Structure (nM) (nM)NMR and MS Data

+++ Compound 1.001: ¹H NMR (400 MHz, CD₃OD) δ8.95 (d, J =6.3 Hz, 0.2 H),8.05 (s, 1 H), 7.94 (d, J =5.5 Hz, 1 H), 7.81 (s, 1 H), 7.64-7.59 (m, 2H), 7.36- 7.30 (m, 2 H), 7.17 (d, J =5.4 Hz, 1 H), 5.00-4.85 (m, 1H),4.80-3.65 (br, 4 H), 2.51 (s, 3 H), 2.60-2.38 (m, 2 H); MS: (ES) m/zcalculated for C₂₀H₁₉FN₈O [M +H]⁺407.2, found 407.

+ Compound 1.002: ¹H NMR (400 MHz, CDCl₃) δ8.64 (s, 1 H), 7.94 (d, J=6.6 Hz, 2 H), 7.85 (d, J =6.6 Hz, 2 H), 7.55 (s, 1 H), 7.50 (s, 1 H),7.44 (d, J =4.3 Hz, 1 H), 7.40-7.30 (m, 2 H), 5.00-4.85 (m, 1H),4.50-4.35 (br, 1 H), 4.30-4.15 (br, 3 H), 2.50-2.38 (m, 1 H), 2.25-2.15(m, 1 H); MS: (ES) m/z calculated for C₂₀H₁₇N₉O [M +H]⁺400.2, found 400.

+++ Compound 1.003: ¹H NMR (400 MHz, CD₃OD) δ9.10 (s, 1 H), 7.91-7.88(m, 2 H), 7.79 (dd, J =1.2, 2.8 Hz, 1 H), 7.74 (d, J =5.9 Hz, 1 H), 7.59(d, J =4.3 Hz, 1 H), 7.34 (t, J =8.6 Hz, 2 H), 6.95 (dd, J =2.8, 4.7 Hz,1 H), 6.86 (d, J =5.5 Hz, 1 H), 5.00-4.85 (m, 1H), 4.80-3.65 (br, 4 H),2.60-2.38 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₈FN₇O [M +H]⁺392.2, found 392.

++ Compound 1.004: ¹H NMR (400 MHz, CD₃OD) δ9.07 (s, 1 H), 8.05 (s, 1H), 7.94 (d, J =5.9 Hz, 1 H), 7.82 (s, 1 H), 7.74 (d, J =8.6 Hz, 2 H),7.38 (d, J =8.6 Hz, 2 H), 7.17 (d, J =5.4 Hz, 1 H), 5.00- 3.65 (br, 5H), 2.60-2.38 (m, 2 H), 2.41 (s, 1 H); MS: (ES) m/z calculated forC₂₀H₂₀N₈O [M +H]⁺389.2, found 389.

+ Compound 1.005: ¹H NMR (400 MHz, CD₃OD) δ9.31 (s, 1 H), 9.15 (d, J=7.0 Hz, 0.5 H), 8.20-8.10 (m, 4 H), 8.05 (s, 1 H), 7.95 (d, J =5.4 Hz,1 H), 7.82 (s, 1 H), 7.18 (d, J =5.8 Hz, 1 H), 5.00-3.65 (br, 5 H), 3.18(s, 3 H), 2.60-2.38 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₂₀N₈O₃S [M+H]⁺453.2, found 453.

+++ Compound 1.006: ¹H NMR (400 MHz, CD₃OD) δ8.96 (d, J =2.7 Hz, 1 H),8.05 (s, 1 H), 7.95-7.82 (m, 3 H), 7.56- 7.38 (m, 3 H), 7.17 (d, J =5.5Hz, 1 H), 5.00-3.65 (br, 5 H), 2.60-2.38 (m, 2 H); MS: (ES) m/zcalculated for C₁₉H₁₇FN₈O [M +H]⁺393.2, found 393.

++ Compound 1.007: ¹H NMR (400 MHz, CD₃OD) δ9.10 (s, 1 H), 7.92 (dd, J =4.7, 7.0 Hz, 2 H), 7.73 (s, 1 H), 7.57 (s, 1 H), 7.54 (d, J =4.3 Hz, 1H), 7.35 (t, J = 8.6 Hz, 2 H), 6.91 (dd, J =2.7, 4.3 Hz, 1 H), 5.00-4.85(m, 1H), 4.60-3.65 (br, 4 H), 3.05-2.95 (m, 1 H), 2.60-2.38 (m, 2 H),1.35 (d, J =7.0 Hz, 6H); MS: (ES) m/z calculated for C₂₃H₂₄FN₇O [M +H]⁺434.2, found 434.

++ Compound 1.008: ¹H NMR (400 MHz, CD₃OD) δ9.14 (s, 1 H), 7.89 (d, J=7.4 Hz, 2 H), 7.73 (s, 1 H), 7.60-7.46 (m, 5 H), 6.90 (dd, J =2.7, 4.3Hz, 1 H), 5.00- 4.80 (m, 1H), 4.60-3.85 (br, 4 H), 3.05- 2.95 (m, 1 H),2.60-2.38 (m, 2 H), 1.35 (d, J =6.6 Hz, 6 H); MS: (ES) m/z calculatedfor C₂₃H₂₅N₇O [M +H]⁺ 416.2, found 416.

+++ Compound 1.009: ¹H NMR (400 MHz, CD₃OD) δ7.72 (d, J =2.4 Hz, 1 H),7.56 (s, 1 H), 7.52 (d, J =4.3 Hz, 1 H), 7.41 (s, 1 H), 6.90-6.87 (m, 1H), 4.95- 4.70 (m, 2 H), 4.60-3.80 (br, 4 H), 3.95- 3.80 (m, 2 H),3.36-3.20 (m, 2 H), 3.05- 2.95 (m, 1 H), 2.60-2.30 (m, 2 H), 1.98- 1.90(m, 2 H), 1.62-1.55 (m, 2 H), 1.35 (d, J =6.6 Hz, 6 H); MS: (ES) m/zcalculated for C₂₃H₃₀N₆O₂S [M +H]⁺ 455.2, found 455.

++ Compound 1.010: ¹H NMR (400 MHz, DMSO) δ9.31 (s, 1 H), 8.92 (d, J=5.9 Hz, 1 H), 7.92-7.85 (m, 3 H), 7.76 (s, 1 H), 7.53 (s, 1 H), 7.41(t, J =9.0 Hz, 2 H), 7.21 (d, J =4.7 Hz, 1 H), 4.65-4.50 (m, 1 H),4.48-3.65 (br, 4 H), 2.30-2.05 (m, 2 H); MS: (ES) m/z calculated forC₁₉H₁₇FN₈O [M +H]⁺393.2, found 393.

+ Compound 1.011:¹H NMR (400 MHz, CD₃OD) δ8.05 (s, 1 H), 8.02 (d, J =9.8Hz, 1 H), 7.94 (d, J =5.5 Hz, 1 H), 7.81 (s, 1 H), 7.5 (d, J =9.8 Hz,1H) 7.18 (d, J =5.8 Hz, 1 H), 4.98-4.80 (m, 1 H), 4.80-3.80 (br, 4 H),4.20-4.10 (m, 2 H), 4.00-3.90 (m, 1 H), 3.55-3.45 (m, 2 H), 2.60-2.35(m, 2 H), 2.05-1.95 (m, 2 H), 1.68-1.55 (m, 2 H); MS: (ES) m/zcalculated for C₂₀H₂₄N₈O₂ [M +H]⁺409.2, found 409.

+++ Compound 1.012: ¹H NMR (400 MHz, CD₃OD) δ7.70 (d, J =2.4 Hz, 1 H),7.52- 7.50 (m, 2 H), 7.41 (s, 1 H), 6.89 (dd, J = 2.4, 4.3 Hz, 1 H),4.95-4.78 (m, 2 H), 4.60- 3.70 (br, 4 H), 3.95-3.80 (m, 2 H), 3.36-3.20(m, 2 H), 2.68 (q, J =7.4 Hz, 2 H), 2.60- 2.30 (m, 2 H), 1.98-1.90 (m, 2H), 1.62-1.55 (m, 2 H), 1.33 (t, J =7.4 Hz, 3 H); MS: (ES) m/zcalculated for C₂₂H₂₈N₆O₂S [M +H]⁺ 441.2, found 441.

+++ Compound 1.013: ¹H NMR (400 MHz, CD₃OD) δ9.10 (s, 1 H), 7.92-7.88(m, 2H), 7.71 (s, 1 H), 7.53 (s, 2 H), 7.35 (t, J =8.8 Hz, 2 H), 6.89(dd, J =2.4, 4.7 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.78-3.80 (br, 4 H), 2.68(q, J =7.4 Hz, 2 H), 2.60-2.35 (m, 2 H), 1.33 (t, J =7.4 Hz, 3 H); MS:(ES) m/z calculated for C₂₂H₂₂FN₇O [M +H]⁺420.2, found 420.

+++ Compound 1.014: ¹H NMR (400 MHz, CD₃OD) δ9.14 (s, 1 H), 8.05 (s, 1H), 7.96-7.88 (m, 2 H), 7.81 (s, 1 H), 7.75- 7.71 (m, 1 H), 7.52 (q, J=8.6 Hz, 1 H), 7.19 (d, J =5.5 Hz, 1 H), 4.98-4.80 (m, 1 H), 4.80-3.80(br, 4 H), 2.62-2.40 (m, 2 H); MS: (ES) m/z calculated for C₁₉H₁₆F₂N₈O[M +H]⁺411.2, found 411.

+++ Compound 1.015: ¹H NMR (400 MHz, CD₃OD) δ9.14 (s, 1 H), 9.05 (d, J=6.7 Hz, 1 H), 7.88 (d, J =7.4 Hz, 2 H), 7.71 (s, 1 H), 7.60-7.46 (m, 5H), 6.89 (dd, J = 2.8, 4.7 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.78-3.80 (br,4 H), 2.68 (q, J =7.4 Hz, 2 H), 2.60-2.40 (m, 2 H), 1.33 (t, J =7.4 Hz,3 H); MS: (ES) m/z calculated for C₂₂H₂₃N₇O [M +H]⁺402.2, found 402.

+++ Compound 1.016: ¹H NMR (400 MHz, DMSO) δ9.45 (s, 1 H), 8.95 (d, J=7.0 Hz, 1 H), 7.87-7.75 (m, 4 H), 7.65 (q, J = 6.2 Hz, 1 H), 7.50 (s, 1H), 7.31 (t, J = 2.4 Hz, 1 H), 7.26 (d, J =4.3 Hz, 1 H), 4.65-4.55 (m, 1H), 4.40-3.75 (br, 4 H), 2.30-2.04 (m, 2 H); MS: (ES) m/z calculated forC₁₉H₁₇FN₈O [M +H]⁺ 393.2, found 393.

+++ Compound 1.017: ¹H NMR (400 MHz, CD₃OD) δ9.03 (d, J =6.7 Hz, 1 H),8.97 (s, 1 H), 7.89 (d, J =8.2 Hz, 2 H), 7.79 (dd, J =1.2, 2.7 Hz, 1 H),7.74 (d, J = 5.9 Hz, 1 H), 7.65-7.50 (m, 4 H), 6.95 (dd, J =2.8, 4.7 Hz,1 H), 6.87 (d, J = 5.9 Hz, 1 H), 5.00-4.80 (m, 1H), 4.70- 3.70 (br, 4H), 2.60-2.38 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₉N₇O [M+H]⁺374.2, found 374.

+ Compound 1.018: ¹H NMR (400 MHz, CD₃OD) δ9.13 (s, 1 H), 8.16 (d, J=2.4 Hz, 1 H), 8.09 (d, J =5.8 Hz, 1 H), 7.86 (d, J =7.8 Hz, 2 H),7.60-7.46 (m, 4 H), 7.19 (d, J =5.5 Hz, 1 H), 4.95-4.80 (m, 1 H),4.78-3.80 (br, 4 H), 2.62-2.40 (m, 2 H); MS: (ES) m/z calculated forC₁₉H₁₈N₈O [M +H]⁺375.2, found 375. +++ Compound 1.019: ¹H NMR (400 MHz,CD₃OD) δ9.55 (s, 1 H), 8.11 (d, J =9.4 Hz, 1 H), 7.98 (d, J =9.4 Hz, 2H), 7.53 (dd, J =1.2, 2.4 Hz, 1 H), 7.55 (d, J = 4.8 Hz, 1 H), 7.50 (s,1 H), 6.89 (dd, J = 2.3, 4.8 Hz, 1 H), 5.00-4.80 (m, 1H), 4.50-3.50 (br,4 H), 2.63 (s, 3 H), 2.60- 2.40 (m, 2 H), 2.31 (d, J =1.1 Hz, 3 H); MS:(ES) m/z calculated for C₂₂H₂₂N₆O

[M +H]⁺387.2, found 387.

+++ Compound 1.020: ¹H NMR (400 MHz, CD₃OD) δ9.10 (s, 1H) 9.07 (d, J=6.2 Hz, 1 H), 7.92-7.88 (m, 2 H), 7.68 (dd, J =1.2, 2.6 Hz, 1 H), 7.53(d, J =4.4 Hz, 1 H), 7.50 (s, 1 H), 7.34 (t, J =8.6 Hz, 2 H), 6.89 (dd,J = 2.4, 4.4 Hz, 1 H), 5.00-4.80 (m, 1H), 4.50- 3.50 (br, 4 H),2.60-2.40 (m, 2 H), 2.31 (d, J = 1.1 Hz, 3 H); MS: (ES) m/z calculatedfor C₂₁H₂₀FN₇O [M +H]⁺406.2, found 406.

+++ Compound 1.021: ¹H NMR (400 MHz, DMSO) δ9.39 (d, J =7.0 Hz, 1H),8.16 (d J =7.0 Hz, 2 H), 7.73 (t, J =7.4 Hz, 1 H), 7.66 (t, J =7.9 Hz, 2H), 7.41 (s, 1 H), 7.37 (s, 1 H), 6.77 (d, J =4.3 Hz, 1 H), 6.56 (dd, J=2 .8, 4.3 Hz, 1 H), 4.63-4.50 (m, 1 H), 4.10-3.75 (br, 4 H), 2.30-2.04(m, 2 H), 2.07 (s, 3 H); MS: (ES) m/z calculated for C₂₁H₂₀N₆O₂ [M+H]⁺389.2, found 389.

+++ Compound 1.022: ¹H NMR (400 MHz, DMSO) δ9.42 (s, 1 H), 8.91 (d, J=6.6 Hz, 1 H), 7.95 (d, J =7.0 Hz, 2 H), 7.67 (d, J =7.0 Hz, 2 H), 7.40(m, 2 H), 6.76 (d, J =4.3 Hz, 1 H), 6.55 (dd, J =2.2, 4.3 Hz, 1 H),4.63-4.50 (m, 1 H), 4.10-3.75 (m, 4 H), 2.30-2.04 (m, 2 H), 2.07 (s, 3H); MS: (ES) m/z calculated for C₂₁H₂₀ClN₇O [M +H]⁺422.2, found 422.

+++ Compound 1.023: ¹H NMR (400 MHz, CD₃OD) δ8.87 (d, J =6.6 Hz, 1H),8.26 (s, 1 H), 8.06-8.03 (m, 2 H), 7.68 (dd, J =1.2, 2.7 Hz, 1 H),7.54-7.45 (m, 5 H), 6.88 (dd, J =2.4, 6.7 Hz, 1 H), 5.00-4.80 (m, 1H),4.50-3.50 (br, 4 H), 2.60-2.40 (m, 2 H), 2.31 (d, J =1.1 Hz, 3 H); MS:(ES) m/z calculated for C₂₂H₂₁N₅OS [M +H]⁺404.2, found 404.

+++ Compound 1.024: ¹H NMR (400 MHz, CD₃OD) δ8.74 (d, J =6.7 Hz, 1 H),8.49 (s, 1 H), 8.10-8.06 (m, 2 H), 7.68 (dd, J =1.2, 2.7 Hz, 1 H),7.57-7.50 (m, 4 H), 6.88 (dd, J =2.7, 4.7 Hz, 1 H), 5.00-4.80 (m, 1H),4.50-3.50 (br, 4 H), 2.58-2.48 (m, 1 H), 2.48-2.38 (br, 1 H), 2.31 (d, J=1.1 Hz, 3 H); MS: (ES) m/z calculated for C₂₂H₂₁N₅O₂ [M +H]⁺ 388.2,found 388.

+++ Compound 1.025: ¹H NMR (400 MHz, CD₃OD) δ7.67 (dd, J =1.2, 2.3 Hz, 1H), 7.52 (d, J =4.6 Hz, 1 H), 7.49 (s, 1 H), 7.36 (s, 1 H), 6.87 (dd, J=2.7, 4.7 Hz, 1 H), 5.00-4.80 (m, 1H), 4.50-3.50 (br, 4 H), 3.50-3.40(m, 3H), 2.58-2.48 (m, 1 H), 2.48-2.38 (br, 1 H), 2.30 (d, J = 0.7 Hz, 3H), 2.10-2.00 (m, 4H); MS: (ES) m/z calculated for C₂₀H₂₄N₆OS [M+H]⁺397.2, found 397.

+++ Compound 1.026: ¹H NMR (400 MHz, DMSO) δ8.03 (d, J =7.1 Hz, 1 H),7.85 (d, J =1.2 Hz, 1 H), 7.74 (d, J =4.7 Hz, 1 H), 7.48 (d, J =0.8 Hz,1 H), 7.41 (s, 1 H), 7.23 (d, J =4.3 Hz, 1 H), 4.53-4.40 (m, 2 H),4.40-3.80 (br, 7 H), 2.40-2.30 (m, 2 H), 2.25-2.10 (m, 1 H), 2.10-2.00(m, 1 H); MS: (ES) m/z calculated for C₁₇H₁₉N₇OS [M +H]⁺370.2, found370.

++ Compound 1.027: ¹H NMR (400 MHz, CDCl₃) δ8.54 (s, 1 H), 7.74 (td, J=1.1, 7.5 Hz, 2 H), 7.56-7.48 (m, 4 H), 7.47-7.40 (m, 2 H), 7.37 (d, J=8.2 Hz, 1 H), 7.33 (d, J = 4.3 Hz, 1 H), 5.00-4.80 (m, 1H), 4.50-4.35(br, 1 H), 4.30-4.15 (br, 3 H), 3.45-3.30 (m, 1H), 2.90-2.75 (m, 1 H),2.50-2.38 (m, 1 H), 2.25-2.15 (m, 1 H); MS: (ES) m/z calculated forC₁₉H₁₈N₈O [M +H]⁺375.2, found 375.

+++ Compound 1.028: ¹H NMR (400 MHz, CD₃OD) δ8.83 (s, 2 H), 7.78 (q, J=1.1 Hz, 1H) 7.73 (d, J =5.8 Hz, 1H) 7.57 (d, J = 3.9 Hz, 1 H), 6.94(dd, J =2.7, 4.7 Hz, 1 H) 6.86 (d, J =5.9 Hz, 1 H), 5.00-4.80 (m, 1H),4.50-3.50 (br, 4 H), 3.20-3.10 (m, 1H), 2.60- 2.48 (m, 1 H), 2.48-2.38(br, 1 H), 2.22-2.12 (m, 2 H), 1.95-1.60 (m, 6 H); MS: (ES) m/zcalculated for C₂₁H₂₄N₆O [M +H]⁺377.2, found 377.

+++ Compound 1.029: ¹H NMR (400 MHz, CD₃OD) δ8.78 (d, J =7.0 Hz, 0.5 H),8.33 (d, J =2.7 Hz, 1 H), 7.87 (td, J =2.4, 9.0 Hz, 2 H), 7.67 (q, J=1.2 Hz, 1 H), 7.51 (td, J =3.1, 9.0 Hz, 4 H), 6.98 (d, J =2.8 Hz, 1 H),6.87 (q, J =2.8, 1.9 Hz, 1 H), 4.50-3.50 (br, 5 H), 2.58-2.48 (m, 1 H),2.48-2.38 (br, 1 H), 2.30 (d, J =0.7 Hz, 3 H); MS: (ES) m/z calculatedfor C₂₂H₂₁ClN₆O [M +H]⁺ 421.2, found 421.

+++ Compound 1.030: ¹H NMR (400 MHz, CD₃OD) δ8.23 (d, J =1.6 Hz, 1 H),8.15 (d, J =1.6 Hz, 1 H), 7.67 (q, J =1.2 Hz, 1 H), 7.62-7.45 (m, 6 H),6.88 (q, J = 2.3 Hz, 1 H), 5.00-4.80 (m, 1H), 4.60- 3.60 (br, 4 H),2.58-2.48 (m, 1 H), 2.48- 2.38 (br, 1 H), 2.30 (d, J =1.1 Hz, 3 H); MS:(ES) m/z calculated for C₂₂H₂₂N₆O [M +H]⁺387.2, found 387.

+++ Compound 1.031: ¹H NMR (400 MHz, DMSO) δ8.35 (d, J =1.2 Hz, 1H) 827(d, J =1.6 Hz, 1 H), 8.24 (d, J =7.4 Hz, 1 H), 7.77 (d, J =0.8 Hz, 1 H),7.73 (t, J =1.2 Hz, 1 H), 7.71 (s, 1 H), 7.57 (s, 1 H), 7.52 (t, J =12.8 Hz, 2 H), 7.44 (d, J =0.8 Hz, 1 H), 7.38 (t, J =7.4 Hz, 1 H),4.60-4.50 (m, 1 H), 4.40-3.80 (br, 4 H), 2.22-2.00 (m, 5 H); MS: (ES)m/z calculated for C₂₁H₂₁N₇O [M +H]⁺388.2, found 388.

+++ Compound 1.032: ¹H NMR (400 MHz, DMSO) δ8.90 (d, J =7.1 Hz, 1 H),7.90 (d, J =8.2 Hz, 2 H), 7.77 (d, J =1.2 Hz, 1 H), 7.58 (t, J =5.8 Hz,3 H), 7.44 (t, J = 8.2 Hz, 2 H), 4.63-4.50 (m, 1 H), 4.40- 3.80 (br, 4H), 2.30-2.05 (m, 5 H); MS: (ES) m/z calculated for C₂₀H₂₀N₈O [M+H]⁺389.2, found 389.

++ Compound 1.033: ¹H NMR (400 MHz, CD₃OD) δ8.93 (s, 2 H), 7.79 (dd, J =1.2, 2.7 Hz, 1 H), 7.74 (d, J =5.9 Hz, 1 H), 7.58 (d, J =3.5 Hz, 1 H),6.94 (dd, J = 2.7, 5.7 Hz, 1 H), 6.87 (d, J =5.9 Hz, 1 H), 5.02-4.95 (q,J =6.6 Hz, 1 H), 4.80-3.60 (br, 5 H), 2.62-2.38 (m, 2 H), 1.53 (d, J=6.6 Hz, 3 H); MS: (ES) m/z calculated for C₁₈H₂₀N₆O₂ [M +H]⁺ 353.2,found 353.

+++ Compound 1.034: ¹H NMR (400 MHz, DMSO) δ8.23 (d, J =7.0 Hz, 1 H),8.17 (s, 1 H), 8.00 (d, J =5.5 Hz, 1 H), 7.81 (s, 1 H), 7.33 (s, 1 H),7.27 (d, J = 5.5 Hz, 1 H), 4.70-4.58 (m, 1 H), 4.57- 3.60 (br, 8 H),2.40-2.05 (m, 2 H), 2.00- 1.80 (m, 4 H); MS: (ES) m/z calculated forC₁₈H₂₁N₇OS [M +H]⁺384.2, found 384.

+++ Compound 1.035: ¹H NMR (400 MHz, DMSO) δ9.20 (s, 1 H), 8.38 (d, J=7.4 Hz, 1 H), 8.35 (d, J =1.2 Hz, 1 H), 8.28 (d, J =1.2 Hz, 1 H), 7.74(m, 3 H), 7.52 (t, J =7.9 Hz, 2 H), 7.38 (t, J =2.4 Hz, 1 H), 7.28 (d, J=4.3 Hz, 1 H), 4.70-4.50 (m, 1 H), 4.40-3.80 (br, 4 H), 2.30-2.05 (m, 2H); MS: (ES) m/z calculated for C₁₉H₁₈N₈O [M +H]⁺375.2, found 375.

+++ Compound 1.036: ¹H NMR (400 MHz, DMSO) δ8.35 (d, J =1.2 Hz, 1 H),8.27 (d, J =1.2 Hz, 1 H), 8.26 (d, J =7.4 Hz, 1 H), 7.87 (d, J =0.8 Hz,1 H), 7.76- 7.70 (m, 3 H), 7.56-7.48 (m, 3 H), 7.38 (t, J =7.8 Hz, 1 H),7.25 (d, J =4.7 Hz, 1 H), 4.70-4.50 (m, 1 H), 4.40-3.80 (br, 4 H),2.30-2.05 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₉N₇O [M +H]⁺ 374.2,found 374.

+++ Compound 1.037: ¹H NMR (400 MHz, CD₃OD) δ7.37 (s, 1 H), 7.28 (q, J=1.2 Hz, 1 H), 7.25 (s, 1 H), 6.86 (d, J =4.3 Hz, 1 H), 6.57 (dd, J=2.7, 4.3 Hz, 1 H), 5.48 (s, 2 H), 4.70-4.60 (m, 1 H), 4.22- 3.78 (m, 8H), 3.28-3.10 (m, 1 H), 2.40- 2.28 (m, 1 H), 2.22-2.12 (m, 4 H), 1.96-1.88 (m, 2 H); 1.62-1.52 (m, 2 H); MS: (ES) m/z calculated forC₂₁H₂₆N₆O₂S [M +H]⁺427.2, found 427.

+++ Compound 1.038: ¹H NMR (400 MHz, DMSO) δ7.96 (d, J =7.4 Hz, 1 H),7.53 (d, J =4.7 Hz, 1 H), 7.50 (q, J =1.2 Hz, 1 H), 7.31 (s, 1 H), 6.94(d, J =4.7 Hz, 1 H), 6.82 (d, J =4.3 Hz, 1 H), 6.61 (q, J =2.3 Hz, 1 H),4.60-4.46 (m, 1 H), 4.10-4.00 (m, 1 H), 3.98-3.84 (m, 1 H), 3.84-3.70(m, 2 H), 3.38 (t, J =6.6 Hz, 4 H), 2.30-2.00 (m, 2 H), 2.00-1.92 (m, 4H); MS: (ES) m/z calculated for C₁₉H₂₂N₆OS [M +H]⁺383.2, found 383.

+++ Compound 1.039: ¹H NMR (400 MHz, CD₃OD) δ8.23 (d, J =1.1 Hz, 1 H),8.15 (d, J =1.6 Hz, 1 H), 7.79 (dd, J =1.2, 2.8 Hz, 1 H), 7.73 (d, J=5.5 Hz, 1 H), 7.64-7.52 (m, 5 H), 7.50-7.42 (m, 1 H), 6.94 (dd, J =2.3, 4.3 Hz, 1 H), 6.86 (d, J =5.5 Hz, 1 H), 5.00-4.80 (m, 1H),4.50-3.50 (br, 4 H), 2.58- 2.48 (m, 1 H), 2.48-2.35 (br, 1 H); MS: (ES)m/z calculated for C₂₁H₂₀N₆O [M +H]⁺ 373.2, found 373.

+++ Compound 1.040: ¹H NMR (400 MHz, CD₃OD) δ9.14 (s, 1 H), 7.88 (td, J=1.2, 6.2 Hz, 2 H), 7.68 (q, J =1.2 Hz. 1 H), 7.62- 7.44 (m, 6 H), 6.88(dd, J =2.3, 4.3 Hz, 1 H), 5.00-4.80 (m, 1H), 4.60-3.60 (br, 4 H),2.60-2.38 (m, 2 H), 2.30 (d, J =1.1 Hz, 3 H); MS: (ES) m/z calculatedfor C₂₁H₂₁N₇O [M +H]⁺388.2, found 388.

+++ Compound 1.041: ¹H NMR (400 MHz, CD₃OD) δ8.75 (d, J =7.0 Hz, 1H)8.28 (d, J =2.7 Hz, 1 H), 7.88 (m, 2 H), 7.68 (q, J = 1.2 Hz, 1 H), 7.52(d, J =4.3 Hz, 1 H), 7.49 (s, 1 H), 7.27-7.22 (m, 2 H), 6.96 (d, J =2.4Hz, 1 H), 6.87 (dd, J =2.7, 4.3 Hz, 1 H), 5.00-4.80 (m, 1H), 4.60-3.60(br, 4 H), 2.60- 2.38 (m, 2 H), 2.30 (d, J =1.1 Hz, 3 H); MS: (ES) m/zcalculated for C₂₂H₂₁FN₆O [M +H]⁺405.2, found 405.

+++ Compound 1.042: ¹H NMR (400 MHz, CD₃OD) δ8.30 (d, J =2.4 Hz, 1H)7.88 (m, 2 H), 7.78 (q, J =1.2 Hz, 1 H), 7.72 (d, J =5.9 Hz, 1 H), 7.55(d, J =3.9 Hz, 1 H), 7.30-7.22 (m, 2 H), 6.99 (d, J =2.7 Hz, 1 H), 6.93(dd, J =2.7, 4.3 Hz, 1 H), 6.83 (d, J =5.5 Hz, 1 H), 4.60-3.80 (br, 4H), 2.90- 2.80 (m, 1 H), 2.78-2.68 (m, 1 H); MS: (ES) m/z calculated forC₂₂H₂₀FN₇O₂ [M +H]⁺ 434.2, found 434.

+ Compound 1.043: ¹H NMR (400 MHz, CD₃OD) δ8.29 (d, J =2.7 Hz, 1 H),7.89 (m, 2 H), 7.78 (dd, J =1.2, 2.7 Hz, 1 H), 7.73 (d, J =5.4 Hz, 1 H),7.55 (d, J =3.5 Hz, 1 H), 7.30-7.22 (m, 2 H), 6.97 (d, J = 2.7 Hz, 1 H),6.94 (dd, J =2.8, 4.3 Hz, 1 H), 6.84 (d, J =5.5 Hz, 1 H), 4.60-3.80 (br,4 H), 2.90-2.82 (m, 1 H), 2.80-2.70 (m, 1 H); MS: (ES) m/z calculatedfor C₂₂H₁₉FN₆O₃ [M +H]⁺435.2, found 435.

+++ Compound 1.044: ¹H NMR (400 MHz, DMSO) δ9.62 (s, 1 H), 9.31 (t, J=3.9 Hz, 1 H), 8.08-8.00 (m, 2 H), 8.00-7.92 (m, 1 H), 7.85 (d, J =5.1Hz, 1 H), 7.29 (d, J =5.0 Hz, 1 H), 4.82-4.70 (m, 1H), 4.70-3.60 (br, 4H), 2.56 (s, 3H), 2.40- 2.20 (br, 2 H); MS: (ES) m/z calculated forC₁₉H₁₈N₈O [M +H]⁺375.2, found 375.

+++ Compound 1.045: ¹H NMR (400 MHz, CD₃OD) δ8.33 (s, 1 H), 8.04 (d, J=1.2 Hz, 1 H), 7.92 (d, J =5.5 Hz, 1 H), 7.81 (d, J =1.2 Hz, 1 H), 7.73(dd, J =1.5, 7.8 Hz, 1 H), 7.42-7.26 (m, 3 H), 7.16 (d, J = 5.5 Hz, 1H), 5.00-4.80 (m, 1H), 4.60- 3.60 (br, 4 H), 2.60-2.38 (m, 2 H), 2.55(s, 3 H); MS: (ES) m/z calculated for C₂₁H₂₀N₆OS [M +H]⁺405.2, found405.

+++ Compound 1.046: ¹H NMR (400 MHz, CD₃OD) δ8.74 (d, J =6.7 Hz, 1 H),8.34 (s, 1 H), 7.78 (dd, J =1.2, 2.7 Hz, 1 H), 7.76- 7.70 (m, 2 H), 7.57(d, J =4.3 Hz, 1 H), 7.42-7.26 (m, 3 H), 6.93 (dd, J =2.8, 4.7 Hz, 1 H),6.84 (d, J =5.9 Hz, 1 H), 5.00-4.80 (m, 1H), 4.60-3.60 (br, 4 H),2.60-2.36 (m, 2 H), 2.55 (s, 3 H); MS: (ES) m/z calculated forC₂₂H₂₁N₅OS [M +H]⁺404.2, found 404.

+ Compound 1.047: ¹H NMR (400 MHz, DMSO) δ7.88 (d, J =7.4 Hz, 1 H), 7.66(s, 1 H), 7.54 (d, J =4.3 Hz, 1 H), 7.29 (s, 1 H), 7.14 (s, 1 H), 7.04(d, J =4.3 Hz, 1 H), 4.65 (s, 1 H), 4.32-4.26 (m, 1 H), 4.20-3.56 (br, 4H), 3.40-3.18 (m, 3 H), 3.08-3.00 (m, 2 H), 2.04-1.94 (m, 1 H),1.90-1.80 (m, 1 H), 1.52-1.42 (m, 1 H), 1.16-0.98 (m, 1 H), 0.31 (d, J=4.3 Hz, 2 H), 0.02 (d, J =5.1 Hz, 2 H); MS: (ES) m/z calculated forC₂₁H₂₅N₇O₂S [M +H]⁺440.2, found 440.

+++ Compound 1.048: ¹H NMR (400 MHz, CD₃OD) δ9.48 (s, 1 H), 8.02 (d, J=1.6 Hz, 2 H), 7.98-7.88 (m, 3 H), 7.78 (s, 1 H), 7.17 (d, J =5.8 Hz, 1H), 5.00-3.80 (br, 4 H), 2.60 (s, 3H), 2.65-2.40 (br, 2 H); MS: (ES) m/zcalculated for C₂₀H₁₉N₇O [M +H]⁺374.2, found 374.

+++ Compound 1.049: ¹H NMR (400 MHz, CD₃OD) δ8.27 (s, 2 H), 7.75 (t, J=1.1, 1 H), 7.70 ((d, J =5.5, 1 H), 7.55 (s, 1 H), 6.91 (dt, J =1.8, 2.6Hz, 1 H), 6.83 (d, J =5.5 Hz, 1 H), 5.00-4.80 (m, 1H), 4.65-3.70 (br, 4H), 3.10 (s, 6 H), 2.60- 2.30 (m, 2 H); MS: (ES) m/z calculated forC₁₈H₂₁N₇O [M +H]⁺352.2, found 352.

+++ Compound 1.050: ¹H NMR (400 MHz, CD₃OD) δ9.12 (s, 1 H), 8.02 (d, J=1.1 Hz, 1 H), 7.90 (d, J =5.9 Hz, 1 H), 7.84 (dd, J =1.5, 8.8 Hz, 2 H),7.79 (s, 1 H), 7.55 (t, J =7.3 Hz, 2 H), 7.46 (t, J =7.3 Hz, 1 H), 7.13(d, J =5.5 Hz, 1 H), 4.02 (s, 2 H), 4.60-3.80 (br, 4 H), 2.80-2.70 (m, 1H), 2.58-2.48 (m, 1 H); MS: (ES) m/z calculated for C₂₀H₂₀N₈O₂ [M +H]⁺405.2, found 405.

+++ Compound 1.051: ¹H NMR (400 MHz, CD₃OD) δ9.12 (s, 1 H), 7.85 (td, J= 1.5, 7.4 Hz, 2 H), 7.76 (d, J =2.2 Hz, 1 H), 7.70 (d, J =5.5 Hz, 2 H),7.55 (m, 2 H), 7.46 (m, 1 H), 6.92 (s, 1 H), 6.83 (d, J =5.5 Hz, 1 H),4.60-3.80 (br, 4 H), 4.02 (s, 2 H), 2.82-2.70 (m, 1 H), 2.58- 2.48 (m, 1H); MS: (ES) m/z calculated for C₂₁H₂₁N₇O₂ [M +H]⁺404.2, found 404. +++Compound 1.052: ¹H NMR (400 MHz, DMSO) δ8.96 (d, J =7.3 Hz, 1.5 H), 8.64(d, J =1.5 Hz, 1 H), 7.52 (d, J =4.8 Hz, 1 H), 7.48 (s, 1 H), 6.93 (d, J=4.7 Hz, 1 H), 6.81 (d, J =4.3 Hz, 1 H), 6.60 (dd, J =2.6, 4.1 Hz, 1 H),4.65-4.55 (m, 1 H), 4.10-4.01 (m, 1 H), 3.95-3.88 (m, 1 H), 3.85-3.78(m, 1 H), 2.48-2.08 (m, 3 H), 1.14-1.10 (m, 2 H), 1.05-1.01 (m, 2 H);MS: (ES) m/z calculated for C₂₁H₂₅N₇O₂S [M +H]⁺

349.2, found 349.

+++ Compound 1.053: ¹H NMR (400 MHz, CD₃OD) δ9.60 (s, 1 H), 8.26 (s, 1H), 8.17 (d, J =9.1 Hz, 1 H), 8.07 (dd, J =1.8, 9.1 Hz, 1 H), 7.76 (d, J=1.5 Hz, 1 H), 7.72 (d, J =5.8 Hz, 1 H), 7.57 (s, 1 H), 6.93 (m, 1 H),6.85 (d, J =5.8 Hz, 1 H), 5.06-4.84 (m, 1 H), 4.82-3.60 (br, 4 H),2.65-2.40 (br, 2 H); MS: (ES) m/z calculated for C₂₀H₁₇ClN₆O [M+H]⁺393.2, found 393.

+++ Compound 1.054: ¹H NMR (400 MHz, CD₃OD) δ9.30 (s, 1 H), 7.91 (d, J=5.8 Hz, 1 H), 7.88 (s, 1 H), 7.40-7.28 (m, 4 H), 7.17 (m, 1 H), 6.95(s, 1 H), 4.94- 4.70 (m, 4 H), 4.24-3.84 (m, 3 H), 2.62- 2.38 (m, 2 H),2.20 (s, 3 H); MS: (ES) m/z calculated for C₂₀H₂₀N₈O [M +H]⁺ 389.2,found 389.

+++ Compound 1.055: ¹H NMR (400 MHz, DMSO) δ8.07 (d, J =7.3 Hz, 1 H),7.51 (d, J =4.8 Hz, 1 H), 7.48 (dd, J =1.4, 2.5 Hz, 1 H), 7.35 (d, J=1.1 Hz, 1 H), 6.93 (d, J =4.8 Hz, 1 H), 6.82 (d, J =4.1 Hz, 1 H), 6.60(dd, J =2.6, 4.4 Hz, 1 H), 5.73 (d, J =1.1 Hz, 1 H), 4.58-4.45 (m, 1 H),4.43 (s, 1 H), ), 4.08-4.00 (m, 1 H), 3.95-3.85 (m, 1 H), 3.82-3.72 (m,2 H), 3.68-3.58 (m, 2 H), 3.40-3.28 (m, 2 H), 2.25-2.05 (m, 2 H),1.60-1.50 (m, 4 H), 1.24 (s, 3 H); MS: (ES) m/z calculated forC₂₁H₂₆N₆O₂S [M +H]⁺ 427.2, found 427.

++ Compound 1.056: ¹H NMR (400 MHz, DMSO) δ8.08 (d, J =7.3 Hz, 1.4H)7.86 (d, J =1.1 Hz, 1H), 7.74 (d, J =4.4 Hz, 1 H), 7.49 (d, J =1.1 Hz, 1H), 7.36 (s, 1 H), 7.24 (d, J =4.8 Hz, 1 H), 5.74 (s, 1 H), 4.58- 4.48(m, 1 H), 4.43 (s, 1 H), 4.38-3.80 (br, 4 H), 3.64-3.54 (m, 2 H),3.40-3.30 (m, 2 H), 2.25-2.05 (m, 2 H), 1.55-1.51 (m, 4 H), 1.15 (s, 3H); MS: (ES) m/z calculated for C₂₀H₂₅N₇O₂S [M +H]⁺427.2, found 427.

+++ Compound 1.057: ¹H NMR (400 MHz, CD₃OD) δ8.58 (d, J =7.3 Hz, 1 H),8.01 (d, J =0.7 Hz, 1 H), 7.92-7.87 (m, 2 H), 7.78 (d, J =1.1 Hz, 1 H),7.40-7.28 (m, 4 H), 7.12 (d, J =5.8 Hz, 1 H), 6.93 (d, J =2.2 Hz, 1 H),4.94-3.80 (m, 5 H), 2.56-2.32 (m, 2 H), 2.20 (s, 3 H); MS: (ES) m/zcalculated for C₂₁H₂₁N₇O [M +H]⁺388.2, found 388.

+++ Compound 1.058: ¹H NMR (400 MHz, CD₃OD) δ8.02 (s, 1 H), 7.90 (d, J=5.5 Hz, 1 H), 7.79 (s, 1 H), 7.35 (s, 2 H), 7.14 (d, J = 5.8 Hz, 1 H),4.60-3.80 (br, 4 H), 3.94 (s, 2 H), 3.90-3.80 (m. 3 H), 3.32-3.20 (m, 2H), 2.75-2.65 (m, 1 H), 2.52-2.45 (m, 1 H), 1.97-1.87 (m, 2 H),1.64-1.50 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₂₅N₇O₃S [M+H]⁺444.2, found 444.

+++ Compound 1.059: ¹H NMR (400 MHz, CD₃OD) δ8.23 (d, J =2.5 Hz, 1 H),8.01 (d, J =1.1 Hz, 1H), 7.89 (d, J =5.7 Hz, 1 H), 7.86-7.82 (m, 2 H),7.78 (s, 1 H), 7.22 (t, J = 8.8 Hz, 2 H), 7.12 (d, J =5.5 Hz, 1 H), 6.91(d, J =2.6 Hz, 1 H), ), 4.60-3.80 (br, 4 H), 4.00 (s, 2 H), 2.80-2.70(m, 1 H), 2.56-2.46 (m, 1 H): MS: (ES) m/z calculated for C₂₁H₂₀FN₇O₂ [M+H]⁺422.2, found 422.

+++ Compound 1.060: ¹H NMR (400 MHz, DMSO) δ8.82 (s, H), 8.51 (s, 1 H),7.56 (s, 2 H), 6.92 (d, J =5.1 Hz, 1 H), 6.66 (s, 1 H), 5.17 (t, J =5.9Hz, 1 H), 4.26 (d, J =1.7 Hz, 1 H), 4.00-3.80 (m, 2 H), 3.75 (d, J = 5.5Hz, 1 H), 3.31 (s, 2 H), 3.10-2.98 (m, 1 H), 2.60-2.48 (m, 1 H),2.28-2.18 (m, 1 H), 1.26 (d, J =6.9 Hz, 6 H); MS: (ES) m/z calculatedfor C₂₀H₂₄N₆O₂ [M +H]⁺381.2, found 381.

++ Compound 1.061: ¹H NMR (400 MHz, CD₃OD) δ9.07 (s, 1 H), 8.80 (s, 2H), 7.66 (d, J =4.7 Hz, 1 H), 7.28 (d, J =4.7 Hz, 1 H), 5.00-3.80 (br, 5H), 3.18-3.00 (m, 1 H), 2.50-2.20 (m, 2 H), 1.34 (d, J =7.0 Hz, 6 H);MS: (ES) m/z calculated for C₁₇H₂₀N₈O [M +H]⁺353.2, found 353.

+++ Compound 1.062: ¹H NMR (400 MHz, CD₃OD) δ8.29 (d, J =2.6 Hz, 1 H),7.89- 7.84 (m, 2 H), 7.77 (d, J =1.5 Hz, 1 H), 7.72 (d, J =5.9 Hz, 1 H),7.57 (d, J =4.4 Hz, 1 H), 7.26 (t, J =8.8 Hz, 2 H), 6.98 (d, J =2.2 Hz,1 H), 6.92 (t, J =3.0 Hz. 1 H), 6.84 (d, J =5.8 Hz, 1 H), 4.85 (m, 1 H),4.64 (m, 1 H), 4.70-3.60 (br, 4 H); MS: (ES) m/z calculated forC₂₁H₁₉FN₆O₂ [M +H]⁺ 407.2, found 407.

++ Compound 1.063: ¹H NMR (400 MHz, CD₃OD) δ8.75 (s, 2 H), 7.76 (s, 1H), 7.71 (d, J =5.5 Hz, 1 H), 7.54 (s, 1 H), 6.91 (s, 1 H), 6.85 (d, J=5.8 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.65-2.30 (br, 2 H), 2.40 (s, 3 H);MS: (ES) m/z calculated for C₁₇H₁₈N₆O [M +H]⁺323.2, found 323.

+++ Compound 1.064: ¹H NMR (400 MHz, DMSO) δ8.97 (d, J =7.3 Hz, 1 H),8.82 (s, 2 H), 7.86 (s, 1 H), 7.74 (d, J =4.8 Hz, 1 H), 7.49 (s, 1 H),7.24 (d, J =4.4 Hz, 1 H), 4.58 (m, 1 H), 4.40-3.80 (br, 4 H), 3.03 (m, 1H), 2.30-2.05 (m, 2 H), 1.26 (d, J =7.0 Hz, 6 H); MS: (ES) m/zcalculated for C₁₈H₂₁N₇O [M +H]⁺ 352.2, found 352.

+++ Compound 1.065: ¹H NMR (400 MHz, CD₃OD) δ8.80 (s, 2 H), 7.76 (m, 1H), 7.71 (d, J =5.8 Hz, 1 H), 7.54 (s, 1 H), 6.92 (dd, J =2.6, 4.4 Hz, 1H), 6.84 (d, J = 5.5 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.81 (q, J =7.4 Hz,2 H), 2.65-2.30 (br, 2 H), 1.33 (t, J =7.4 Hz, 3 H); MS: (ES) m/zcalculated for C₁₇H₁₈N₆O [M +H]⁺ 337.2, found 337.

+++ Compound 1.066: ¹H NMR (400 MHz, CD₃OD) δ9.31 (s, 1 H), 8.85 (d, J=3.6 Hz, 1 H), 8.24 (s, 1 H), 8.02 (d, J =3.6 Hz, 2 H), 7.92 (d, J =5.4Hz, 1 H), 7.47 (s, 3 H), 7.19 (d, J =5.4 Hz, 1 H), 5.00- 3.80 (m, 5 H),2.60-2.40 (m, 2 H); MS: (ES) m/z calculated for C₁₉H₁₇N₇OS [M +H]⁺392.2,found 392.

+++ Compound 1.067: ¹H NMR (400 MHz, DMSO) δ8.55 (d, J =7.0 Hz, 1 H),8.52 (d, J =2.6 Hz, 1 H), 8.46 (s, 1 H), 8.13 (d, J =4.4 Hz, 1 H),7.97-7.92 (m, 2 H), 7.57 (d, J =4.4 Hz, 1 H), 7.36 (t, J =6.6 Hz, 2 H),6.89 (d, J =2.2 Hz, 1 H), 4.66- 4.58 (m, 1 H), 4.58-3.60 (br, 4 H),2.38- 2.05 (m, 2 H); MS: (ES) m/z calculated for C₁₉H₁₇FN₈O [M+H]⁺393.2, found 393.

+++ Compound 1.068: ¹H NMR (400 MHz, CD₃OD) δ8.82 (d, J =6.3 Hz, 1 H),8.23 (s, 1 H), 8.03-8.01 (m, 3 H), 7.92- 7.90 (m, 1 H), 7.88 (s, 1 H),7.48-7.45 (m, 3 H), 7.15 (d, J =5.8 Hz, 1 H), 4.98- 3.80 (m, 5 H),2.60-2.40 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₈N₆OS [M +H]⁺391.2,found 391.

+++ Compound 1.069: ¹H NMR (400 MHz, CD₃OD) δ9.26 (s, 1 H), 8.70 (d, J=5.9 Hz, 0.5 H), 8.45 (s, 1 H), 8.04 (d, J =5.5 Hz, 2 H), 7.86 (d, J=5.5 Hz, 1 H), 7.49 (m, 3 H), 7.21 (d, J =5.5 Hz, 1 H), 5.00- 3.80 (m, 5H), 2.60-2.38 (m, 2 H); MS: (ES) m/z calculated for C₁₉H₁₇N₇O₂ [M+H]⁺376.2, found 376.

+++ Compound 1.070: ¹H NMR (400 MHz, CD₃OD) δ8.71 (d, J =6.3 Hz, 1 H),8.46 (s, 1 H), 8.06-8.02 (m, 3 H), 7.91 (d, J =5.5 Hz, 1 H), 7.80 (s, 1H), 7.49 (m, 3 H), 7.15 (d, J =5.9 Hz, 1 H), 5.00- 3.80 (m, 5 H),2.60-2.38 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₈N₆O₂ [M +H]⁺375.2,found 375.

+++ Compound 1.071: ¹H NMR (400 MHz, CD₃OD) δ8.64 (s, 2 H), 7.76 (m, 1H), 7.71 (d, J =5.4 Hz, 1 H), 7.54 (s, 1 H), 6.92 (dd, J =2.6, 4.4 Hz, 1H), 6.84 (d, J = 5.5 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.65-2.30 (br, 2 H),2.07-2.02 (m, 1 H), 1.23-1.18 (m, 2 H), 0.96-0.91 (m, 2 H); MS: (ES) m/zcalculated for C₁₉H₂₀N₆O [M +H]⁺349.2, found 349.

+++ Compound 1.072: ¹H NMR (400 MHz, CD₃OD) δ8.07 (s, 1 H), 7.80-7.76(m, 1 H), 7.72 (d, J =5.6 Hz, 1 H), 7.56 (d, J =4.4 Hz, 1 H), 7.37 (s, 1H), 6.94 (dd, J =2.4, 4.4 Hz, 1 H), 6.85 (d, J =6.0 Hz, 1 H), 4.80- 4.60(br, 1 H), 4.50-4.20 (br, 2 H), 4.02-3.80 (m, 4 H), 3.35-3.25 (m, 4 H),2.78-2.66 (m, 1 H), 2.56-2.45 (m, 1 H), 1.98-1.88 (m, 2 H), 1.64-1.52(m, 2 H); MS: (ES) m/z calculated for C₂₁H₂₆N₆O₃S [M +H]⁺ 443.2, found443.

+++ Compound 1.073: ¹H NMR (400 MHz, CD₃OD) δ8.22 (d, J =2.6 Hz, 1 H),7.86- 7.82 (m, 2 H), 7.42 (d, J =4.7 Hz, 1 H), 7.38 (t, J =1.5 Hz, 1 H),7.21 (dt, J =2.2, 8.4 Hz, 2 H), 6.98 (d, J =4.4 Hz, 1 H), 6.91 (d, J=2.5 Hz, 1 H), 6.86 (d, J =4.7 Hz, 1 H), 6.64 (dd, J =2.5, 4.0 Hz, 1 H),4.34 (d, J =11.4 Hz, 1 H), 4.15 (d, J =11.4 Hz, 1 H), 4.02-3.88 (m, 4H), 2.65-2.55 (m, 1 H), 2.45-2.36 (m, 1 H); MS: (ES) m/z calculated forC₂₂H₂₁FN₆O₂ [M +H]⁺421.2, found 421.

+++ Compound 1.074: ¹H NMR (400 MHz, CD₃OD) δ8.28 (d, J =2.5 Hz, 1H)7.85 (dd, J =2.2, 6.9 Hz, 2 H), 7.48 (dd, J =2.2, 6.9 Hz, 2 H), 7.42 (d,J =5.2 Hz, 1 H), 7.39 (dd, J =1.1, 2.6 Hz, 1 H), 6.98 (d, J =4.4 Hz, 1H), 6.93 (d, J =2.6 Hz, 1 H), 6.86 (d, J =5.1 Hz, 1 H), 6.65 (dd, J=2.5, 4.1 Hz, 1 H), 4.34 (d, J =11.4 Hz, 1 H),4.15 (d, J = 11.4 Hz, 1H), 4.02-3.88 (m, 4 H), 2.65-2.55 (m, 1 H), 2.45-2.36 (m, 1 H); MS: (ES)m/z calculated for C₂₂H₂₁ClN₆O₂ [M +H]⁺ 437.2, found 437.

++ + Compound 1.075: ¹H NMR (400 MHz, CD₃OD) δ8.64 (s, 1 H), 8.17 (s, 1H), 7.75 (s, 1 H), 7.66 (d, J =4.8 Hz, 1 H), 7.51 (s, 1 H), 7.22 (d, J=4.4 Hz, 1 H), 4.75--4.68 (m, 1 H), 4.40-4.32 (m, 1 H), 4.30-3.80 (m, 4H), 3.40-3.20 (m, 4 H), 2.42-2.32 (m, 1 H), 2.26-2.16 (m, 1 H),1.98-1.90 (m, 2 H), 1.58-1.50 (m, 2 H); MS: (ES) m/z calculated forC₂₀H₂₄N₈O₂ [M +H]⁺409.2, found 409.

+++ +++ Compound 1.076: ¹H NMR (400 MHz, CD₃OD) δ9.17 (s, 2 H), 7.83 (m,3 H), 7.71 (d, J =5.4 Hz, 1 H), 7.56 (s, 1 H), 7.31 (t, J = 8.5 Hz, 2H), 6.92 (s, 1 H), 6.85 (d, J =5.9 Hz, 1 H), 5.00-3.60 (br, 5 H),2.65-2.30 (br, 2 H); MS: (ES) m/z calculated for C₂₂H₁₉FN₆O [M+H]⁺403.2, found 403.

+++ +++ Compound 1.077: ¹H NMR (400 MHz, CD₃OD) δ8.81 (s, 2 H), 7.76 (s,1 H), 7.71 (d, J =5.8 Hz, 1 H), 7.55 (s, 1 H), 6.92 (s, 1 H), 6.84 (d, J=5.9 Hz, 1 H), 5.00-3.60 (br, 5 H), 3.18-3.00 (m, 1 H), 2.65-2.30 (br, 2H), 1.36 (d, J =7.0 Hz, 6 H); MS: (ES) m/z calculated for C₁₉H₂₂N₆O [M+H]⁺351.2, found 351.

+++ +++ Compound 1.078: ¹H NMR (400 MHz, CD₃OD) δ9.06 (s, 1H) 7.64 (d, J=4.8 Hz, 1 H), 7.36 (s, 1 H), 7.26 (d, J =4.8 Hz, 1 H), 4.73-4.68 (m, 1H), 4.60-3.60 (br, 4 H), 3.96-3.80 (m, 3 H), 3.35-3.20 (m, 2 H),2.45-2.35 (m, 1 H), 2.30-2.18 (m, 1 H), 1.95-1.88 (m, 2 H), 1.62-1.50(m, 2 H); MS: (ES) m/z calculated for C₁₈H₂₂N₈O₂S [M +H]⁺415.2, found415.

+++ +++ Compound 1.079: ¹H NMR (400 MHz, CD₃OD) δ7.74 (s, 1 H), 7.66 (d,J =4.7 Hz, 1 H), 7.50 (s, 1 H), 7.36 (s, 1 H), 7.22 (d, J = 4.9 Hz, 1H), 4.76-4.65 (m, 1 H), 4.40-4.30 (m, 1 H), 4.20-3.75 (m, 4 H),3.40-3.20 (m, 4 H), 2.42-2.10 (m, 2 H), 1.95-1.85 (m, 2 H), 1.65-1.50(m, 2 H); MS: (ES) m/z calculated for C₁₉H₂₃N₇O₂S [M +H]⁺414.2, found414.

+++ ++ Compound 1.080: ¹H NMR (400 MHz, CD₃OD) δ8.61 (d, J =6.2 Hz, 1H), 8.49 (s, 1 H), 7.94 (d, J =7.7 Hz, 1 H), 7.76 (d, J = 1.1 Hz, 1 H),7.71 (d, J =5.4 Hz, 1 H), 7.56 (d, J =2.9 Hz, 1 H), 7.40-7.26 (m, 3 H),6.92 (dt, J =1.8, 2.6 Hz, 1 H), 6.83 (d, J = 5.5 Hz, 1 H), 5.00-3.60 (m,5 H), 2.66 (s, 3 H), 2.60-2.38 (m, 2 H); MS: (ES) m/z calculated forC₂₂H₂₁N₅O₂ [M +H]⁺ 388.2, found 388.

+++ ++ Compound 1.081: ¹H NMR (400 MHz, CD₃OD) δ8.61 (s, 1 H), 8.44 (s,1 H), 8.07 (d, J =8.8 Hz, 1 H), 7.99 (d, J =8.8 Hz, 1 H), 7.77 (s, 1 H),7.72 (d, J =5.9 Hz, 1 H), 7.57 (d, J =4.4 Hz, 1 H), 6.96 (s, 1 H), 6.94-6.91 (m, 1 H), 6.85 (d, J =5.9 Hz, 1 H), 5.00-3.65 (br, 5 H), 2.60-2.30(m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₈ClN₇O [M +H]⁺408.2, found408.

+++ ++ Compound 1.082: ¹H NMR (400 MHz, CD₃OD) δ9.28 (d, J =5.5 Hz, 1H), 7.77 (s, 1 H), 7.72 (d, J =5.9 Hz, 1 H), 7.55 (s, 1 H), 6.92 (s, 1H), 6.85 (d, J =5.5 Hz, 1 H), 4.80- 3.65 (m, 5 H), 3.99 (d, J =7.0 Hz, 2H), 3.59 (t, J =11.0 Hz, 2 H), 3.41-3.29 (m, 1 H), 2.60-2.30 (m, 2 H),2.10-1.85 (m, 4 H); MS: (ES) m/z calculated for C₁₉H₂₂N₆O₃ [M +H]⁺383.2,found 383.

+++ ++ Compound 1.083: ¹H NMR (400 MHz, DMSO) δ11.40 (s, 1 H), 8.05 (d,J =7.0 Hz, 2 H), 7.91 (s, 1 H), 7.84 (d, J =4.4 Hz, 1 H), 7.60-7.40 (m,4 H), 7.00-6.90 (m, 2 H), 4.85-3.50 (br, 5 H), 2.45-2.20 (m, 2 H); MS:(ES) m/z calculated for C₂₀H₁₉N₇O [M +H]⁺374.2, found 374.

+++ +++ Compound 1.084: ¹H NMR (400 MHz, DMSO) δ9.20 (s, 1 H), 8.57 (d,J =7.0 Hz, 1 H), 8.52 (d, J =2.2 Hz, 1 H), 7.97-7.93 (m, 2 H), 7.74 (d,J =4.4 Hz, 1 H), 7.38 (t, J =8.8 Hz, 2 H), 7.28 (d, J =4.4 Hz, 1 H),6.90 (d, J =2.5 Hz, 1 H), 4.70-3.50 (m, 5 H), 2.40-2.10 (m, 2 H); MS:(ES) m/z calculated for C₁₉H₁₇FN₈O [M +H]⁺ 393.2, found 393.

+++ +++ Compound 1.085: ¹H NMR (400 MHz, CD₃OD) δ9.49 (s, 1 H), 8.04 (d,J =9.1 Hz, 1 H), 7.93 (d, J =6.9 Hz, 2 H), 7.75 (d, J = 1.5 Hz, 1 H),7.70 (d, J =5.9 Hz, 1 H), 7.55 (s, 1 H), 6.92 (s, 1 H), 6.85 (d, J =5.5Hz, 1 H), 5.00-3.70 (m, 5 H), 3.30 (s, 3 H), 2.60- 2.30 (m, 2 H); MS:(ES) m/z calculated for C₂₁H₂₀N₆O [M +H]⁺373.2, found 373.

++ ++ Compound 1.086: ¹H NMR (400 MHz, CD₃OD) δ8.02 (s, 1 H), 7.90 (d, J=5.9 Hz, 1 H), 7.79 (s, 1 H), 7.73 (d, J =2.5 Hz, 1 H), 7.14 (d, J =5.5Hz, 1 H), 6.72 (d, J =2.6 Hz, 1 H), 5.00-3.70 (m, 8 H), 3.55 (dt, J =2.2, 11.7 Hz, 2 H), 2.60-2.30 (m, 2 H), 2.20- 1.95 (m, 4 H); MS: (ES)m/z calculated for C₁₉H₂₃N₇O₂ [M +H]⁺382.2, found 382.

+ ++ Compound 1.087: ¹H NMR (400 MHz, CD₃OD) δ9.25 (s, 1 H), 7.85 (d, J=5.1 Hz, 1 H), 7.73 (d, J =2.6 Hz, 1 H), 7.20 (d, J = 5.5 Hz, 1 H), 6.73(d, J =2.5 Hz, 1 H), 5.00- 3.60 (m, 8 H), 3.55 (dt, J =2.2, 11.7 Hz, 2H), 2.60-2.39 (m, 2 H), 2.20-1.95 (m, 4 H); MS: (ES) m/z calculated forC₁₈H₂₂N₈O₂ [M +H]⁺383.2, found 383.

+++ +++ Compound 1.088: ¹H NMR (400 MHz, CD₃OD) δ8.48 (d, J =6.2 Hz, 1H), 7.78- 7.70 (m, 3 H), 7.55 (s, 1 H), 6.91 (dd, J = 2.5, 4.4 Hz, 1 H),6.83 (d, J =5.5 Hz, 1 H), 6.73 (d, J =2.2 Hz, 1 H), 5.00-3.60 (m, 8 H),3.55 (dt, J =2.2, 11.7 Hz, 2 H), 2.60- 2.39 (m, 2 H), 2.20-1.95 (m, 4H); MS: (ES) m/z calculated for C₂₀H₂₄N₆O₂ [M +H]⁺ 381.2, found 381.

+++ +++ Compound 1.089: ¹H NMR (400 MHz, DMSO) δ9.35 (s, 1 H), 9.20 (s,1 H), 8.99 (d, J =7.0 Hz, 1.5 H), 7.95-7.91 (m, 2 H), 7.75 (d, J =4.4Hz, 1 H), 7.45 (t, J =8.5 Hz, 2 H), 7.28 (d, .J =4.4 Hz, 1 H), 4.80-3.50(m, 5 H), 2.40-2.10 (m, 2 H); MS: (ES) m/z calculated for C₁₈H₁₆FN₉O [M+H]⁺ 394.2, found 394.

+++ +++ Compound 1.090: ¹H NMR (400 MHz, DMSO) δ9.34 (s, 1 H), 8.91 (d,J =8.0 Hz, 1 H), 7.95-7.91 (m, 2 H), 7.86 (s, 1 H), 7.75 (d, J =4.8 Hz,1 H), 7.50 (s, 1 H), 7.45 (t, J =7.0 Hz, 2 H), 7.25 (d, J =4.8 Hz, 1 H),4.65-4.56 (m, 1 H), 4.50-3.70 (m, 4 H), 2.30-2.10 (m, 2 H); MS: (ES) m/zcalculated for C₁₉H₁₇FN₈O [M +H]⁺393.2. found 393.

+++ +++ Compound 1.091: ¹H NMR (400 MHz, DMSO) δ9.39 (s, 1 H), 8.92 (d,J =7.0 Hz, 1 H), 7.90-7.86 (m, 2 H), 7.75 (d, J =4.4 Hz, 1 H), 7.58 (t,J =7.4 Hz, 2 H), 7.50 (s, 1 H), 7.46 (t, J =7.4 Hz, 1 H), 7.25 (d, J=4.4 Hz, 1 H), 4.62-4.50 (m, 1 H), 4.50-3.70 (m, 4 H), 2.30-2.00 (m, 2H); MS: (ES) m/z calculated for C₁₉H₁₈N₈O [M +H]⁺375.2, found 375.

+++ +++ Compound 1.092: ¹H NMR (400 MHz, DMSO) δ8.52 (d, J =7.7 Hz, 2H), 7.97 (m, 2 H), 7.86 (s, 1 H), 7.75 (d, J =4.1 Hz, 1 H), 7.50 (s, 1H), 7.37 (t, J =7.0 Hz, 2 H), 7.25 (d, J =4.4 Hz, 1 H), 6.89 (s, 1 H),4.62-4.50 (m, 1 H), 4.50-3.70 (m, 4 H), 2.30-2.00 (m, 2 H); MS: (ES) m/zcalculated for C₂₀H₁₈FN₇O [M +H]⁺392.2, found 392.

+++ +++ Compound 1.093: ¹H NMR (400 MHz, CD₃OD) δ9.42 (d, J =7.0 Hz, 0.8H), 9.18 (s, 2 H), 7.77-7.70 (m, 4 H), 7.58-7.48 (m, 4 H), 6.93 (dd, J=2.6, 4.4 Hz, 1 H), 6.85 (d, J =5.5 Hz, 1 H), 5.00-3.65 (br, 5 H), 2.65-2.40 (m, 2 H): MS: (ES) m/z calculated for C₂₂H₂₀N₆O [M +H]⁺385.2, found385.

+++ +++ Compound 1.094: ¹H NMR (400 MHz, DMSO) δ8.47 (d, J =7.0 Hz, 1H), 8.10 (d, J =2.2 Hz, 1 H), 7.52-7.40 (m, 4 H), 6.93 (d, J =4.4 Hz, 1H), 6.87 (d, J =2.2 Hz, 1 H), 6.80 (d, J =4.0 Hz, 1 H), 6.60 (dd, J =2.9, 4.0 Hz, 1 H), 4.62-4.50 (m, 1 H), 4.10- 3.70 (m, 4 H), 2.19 (s, 3H), 2.30-2.00 (m, 2 H); MS: (ES) m/z calculated for C₂₂H₂₁ClN₆O [M+H]⁺421.2, found 421.

+++ +++ Compound 1.095: ¹H NMR (400 MHz, DMSO) δ8.70 (s, 1 H), 8.53 (d,J =7.0 Hz, 1 H), 8.10 (dd, J =5.5, 8.8 Hz, 2 H), 7.53 (d, J =4.8 Hz, 1H), 7.49 (s, 1 H), 7.41 (t, J = 8.8 Hz, 1 H), 6.95 (d, J =4.4 Hz, 1 H),6.83 (d, J =4.0 Hz, 1 H), 6.62 (dd, J =2.6, 4.1 Hz, 1 H), 4.62-4.50 (m,1 H), 4.10-3.70 (m, 4 H), 2.30-2.00 (m, 2 H): MS: (ES) m/z calculatedfor C₂₁H₁₈FN₅O₂ [M +H]⁺392.2, found 392.

+++ +++ Compound 1.096: ¹H NMR (400 MHz, CD₃OD) δ8.85 (d, J =6.6 Hz, 1H), 8.23 (s, 1 H), 8.09-8.05 (m, 2 H), 7.76 (s, 1 H), 7.72 (d, J =5.9Hz, 1 H), 7.56 (s, 1 H), 7.23 (t, J =8.8 Hz, 1 H), 6.93 (dd, J =2.5, 4.4Hz, 1 H), 6.85 (d, J =5.9 Hz, 1 H), 5.00-3.60 (m, 5 H), 2.60-2.35 (m, 2H); MS: (ES) m/z calculated for C₂₁H₁₈FN₅OS [M +H]⁺ 408.2, found 408.

+++ +++ Compound 1.097: ¹H NMR (400 MHz, CD₃OD) δ7.68-7.65 (m, 2 H),7.38 (s, 1 H), 6.76-6.74 (m, 2 H), 4.75-4.65 (m, 1 H), 4.25-4.15 (m, 1H), 4.06-3.80 (m, 5 H), 3.35-3.20 (m, 3 H), 2.62 (s, 1 H), 2.50-2.30 (m,2 H), 1.98-1.90 (m, 2 H), 1.65-1.52 (m, 2 H); MS: (ES) m/z calculatedfor C₂₁H₂₆N₆O₂S [M +H]⁺427.2, found 427.

+++ +++ Compound 1.098: ¹H NMR (400 MHz, CD₃OD) δ7.76 (s, 1 H), 7.70 (d,J =5.8 Hz, 1 H), 7.54 (d, J =3.7 Hz, 1 H), 7.39 (s, 1H), 7.53 (dd, J=2.5, 4.0 Hz, 1 H), 6.84 (d, J = 5.5 Hz, 1 H), 4.82-4.75 (m, 1 H),4.70-3.60 (br, 4 H), 3.90-3.80 (m, 2 H), 3.40-3.20 (m, 3 H), 2.52-2.30(m, 2 H), 1.96-1.90 (m, 2 H), 1.65-1.52 (m, 2 H); MS: (ES) m/zcalculated for C₂₀H₂₄FN₆O₂S [M +H]⁺413.2, found 413.

+++ +++ Compound 1.099: ¹H NMR (400 MHz, CD₃OD) δ8.35 (d, J =2.6 Hz, 1H), 7.76- 7.64 (m, 3 H), 7.53 (dt, J =6.2, 8.4 Hz, 2 H), 7.13 (dt, J=2.5, 8.4 Hz, 1 H), 6.95 (d, J =2.6 Hz, 1 H), 6.77-6.73 (m, 2 H), 4.82-4.75 (m, 1 H), 4.30-4.24 (m, 1 H), 4.08-3.92 (m, 3 H), 2.63 (s, 3 H),2.52-2.30 (m, 2 H); MS: (ES) m/z calculated for C₂₂H₂₁FN₆O [M +H]⁺405.2,found 405.

+++ + Compound 1.100: ¹H NMR (400 MHz, CD₃OD) δ8.36 (d, J =2.6 Hz, 1 H),7.90 (dd, J =2.6, 10.3 Hz, 1 H ), 7.72-7.64 (m, 3 H), 7.61 (t, J =8.0Hz, 1 H), 6.95 (d, J =2.6 Hz, 1 H), 6.77-6.73 (m, 2 H), 4.82-4.75 (m, 1H), 4.30-4.24 (m, 1 H), 4.08-3.92 (m, 3 H), 2.63 (s, 3 H), 2.52-2.30 (m,2 H); MS: (ES) m/z calculated for C₂₂H₂₀ClFN₆O [M +H]⁺439.2, found 439.

+++ ++ Compound 1.101: ¹H NMR (400 MHz, CD₃OD) δ8.02 (d, J =2.2 Hz, 1H), 7.65- 7.57 (m, 3 H), 7.54-7.46 (m, 3 H), 6.97 (d, J =2.2 Hz, 1 H),6.75-6.72 (m, 2 H), 4.82- 4.75 (m, 1 H), 4.28-4.24 (m, 1 H), 4.08-4.00(m, 1 H), 3.98-3.90 (m, 4 H), 2.61 (s, 3 H), 2.52-2.30 (m, 2 H); MS:(ES) m/z calculated for C₂₄H₂₃N₇O [M +H]⁺426.2, found 426.

+++ +++ Compound 1.102: ¹H NMR (400 MHz, DMSO) δ8.58 (d, J =2.6 Hz, 1H), 8.55 (d, J =6.9 Hz, 1 H), 7.97 (dd, J =2.2, 7.0 Hz, 2 H), 7.86 (s, 1H), 7.75 (d, J =4.4 Hz, 1 H), 7.58 (dd, J =2.2, 6.9 Hz, 2 H), 7.50 (s, 1H), 7.25 (d, J =4.4 Hz, 1 H), 6.91 (d, J =2.6 Hz, 1 H), 4.62-4.50 (m, 1H), 4.50-3.70 (m, 4 H), 2.30-2.00 (m, 2 H); MS: (ES) m/z calculated forC₂₀H₁₈ClN₇O [M +H]⁺ 408.2, found 408.

+++ ++ Compound 1.103: ¹H NMR (400 MHz, DMSO) δ8.44 (d, J =7.3 Hz, 1H)8.10 (d, J =2.2 Hz, 1 H), 7.62 (d, J =4.8, 2 H), 7.53 (s, 1 H),7.46-7.40 (m, 2 H), 6.87 (d, J =4.8 Hz, 1 H), 6.85 (d, 2.6 Hz, 1 H),6.49 (d, J =2.2 Hz, 1 H), 4.48-4.40 (m, 1 H), 3.70- 3.50 (m, 4 H), 2.45(s, 3 H), 2.20 (s, 3 H), 2.20-1.90 (m, 2 H); MS: (ES) m/z calculated forC₂₃H₂₃ClN₆O [M +H]⁺435.2, found 435.

+++ + Compound 1.104: ¹H NMR (400 MHz, DMSO) δ11.38 (s, 1H) 8.78 (d, J=7.0 Hz, 1 H), 8.59 (d, J =3.0 Hz, 1 H), 7.95 (d, J =7.0, 2 H), 7.81 (m,2 H), 7.61 (d, J =8.8 Hz, 2 H), 6.92 (s, 1 H), 6.85 (d, J =5.5 Hz, 1 H),6.76 (d, J =2.2 Hz, 1 H), 4.70-4.65 (m, 1 H), 4.18-3.80 (m, 4H), 2.48(s, 3 H), 2.38-2.18 (m, 2 H); MS: (ES) m/z calculated for C₂₂H₂₁ClN₆O [M+H]⁺421.2, found 421.

+++ ++ Compound 1.105: ¹H NMR (400 MHz, DMSO) δ11.28 (s, 1 H), 8.82 (d,J =7.0 Hz, 1 H), 8.33 (s, 1 H), 8.04-8.01 (m, 2 H), 7.82 (m, 2 H),7.54-7.50 (m, 3 H), 6.86 (d, J =5.5 Hz, 1 H), 6.76 (d, J =2.2 Hz, 1 H),4.75-4.65 (m, 1 H), 4.20-3.60 (m, 4 H), 2.48 (s, 3 H), 2.40-2.20 (m, 2H); MS: (ES) m/z calculated for C₂₂H₂₁N₅OS [M +H]⁺404.2, found 404.

+++ ++ Compound 1.106: ¹H NMR (400 MHz, CDCCl₃) δ7.91 (d, J =7.3 Hz, 1H), 7.82 (s, 1 H), 7.68 (dd, J =4.4, 8.8 Hz, 2 H), 7.33 (d, J =4.8 Hz, 1H), 7.19 (t, J =8.8 Hz, 3 H), 7.00 (m, 2 H), 6.50 (s, 1 H), 4.75 (s, 1H), 3.90-3.56 (m, 4 H), 2.57 (s, 3 H), 2.42- 2.38 (m, 1 H), 2.02-1.80(m, 1 H); MS: (ES) m/z calculated for C₂₂H₂₁FN₆O [M +H]⁺ 405.2, found405.

+++ ++ Compound 1.107: ¹H NMR (400 MHz, CD₃OD) δ8.72 (d, J =8.1 Hz, 1H), 8.45 (s, 1 H), 8.06 (d, J =8.1 Hz, 2 H), 7.67 (d, J = 5.5 Hz, 2 H),7.52 (m, 3 H), 6.76-6.73 (m, 2 H), 4.85-4.75 (m, 1 H), 4.30-4.22 (m, 1H), 4.10-3.90 (m, 3 H), 2.64 (s, 3 H), 2.55-2.35 (m, 2 H); MS: (ES) m/zcalculated for C₂₂H₂₁N₅O₂ [M +H]⁺388.2, found 388.

+++ ++ Compound 1.108: ¹H NMR (400 MHz, CD₃OD) δ8.22 (s, 1 H), 8.09 (dd,J =5.1, 8.8 Hz, 2 H), 7.67 (d, J =5.5 Hz, 2 H), 7.24 (t, J =8.8 Hz, 2H), 6.75 (d, J =5.5 Hz, 2 H), 4.85-4.75 (m, 1 H), 4.30-4.22 (m, 1 H),4.10-3.90 (m, 3 H), 2.64 (s, 3 H), 2.55-2.35 (m, 2 H); MS: (ES) m/zcalculated for C₂₂H₂₀FN₅OS [M +H]⁺422.2, found 422.

+++ ++ Compound 1.109: ¹H NMR (400 MHz, CD₃OD) δ7.87 (s, 1 H), 7.64 (m,2 H), 7.40-7.28 (m, 4 H), 6.93 (s, 1 H), 6.74-6.70 (m, 2 H), 4.80-4.70(m, 1 H), 4.30-4.20 (m, 1 H), 4.10-3.85 (m, 3 H), 2.61 (s, 3 H), 2.50-2.35 (m, 2 H), 2.20 (s, 3 H); MS: (ES) m/z calculated for C₂₃H₂₄N₅O [M+H]⁺401.2, found 401.

+++ ++ Compound 1.110: ¹H NMR (400 MHz, CD₃OD) δ9.18 (s, 2 H), 7.77 (d,J =7.0 Hz, 2 H), 7.67 (d, J =5.9 Hz, 2 H), 7.57-7.48 (m, 3 H), 6.76-6.72(m, 2 H), 4.95-4.80 (m, 1 H), 4.32-4.24 (m, 1 H), 4.10-3.90 (m, 3 H),2.64 (s, 3 H), 2.50-2.35 (m, 2 H); MS: (ES) m/z calculated for C₂₃H₂₂N₆O[M +H]⁺399.2, found 399.

+++ ++ Compound 1.111: ¹H NMR (400 MHz, DMSO) δ9.37 (d, J =7.0 Hz, 1H),8.16 (d, J =7.0 Hz, 2 H), 7.75-7.62 (m, 4 H), 7.47 (d, J =2.6 Hz, 1 H),6.93 (d, J =4.7 Hz, 1 H), 6.51 (d, J =2.6 Hz, 1 H), 4.53-4.48 (m, 1 H),3.80-3.55 (m, 4 H), 2.48 (s, 3 H), 2.28- 1.90 (m, 2 H); MS: (ES) m/zcalculated for C₂₁H₂₀N₆O₂ [M +H]⁺389.2, found 389.

+++ ++ Compound 1.112: ¹H NMR (400 MHz, DMSO) δ9.20 (s, 1 H), 8.61 (m, 2H), 7.98- 7.94 (m, 2 H), 7.74 (d, J =4.4 Hz, 1 H), 7.59-7.55 (m, 2 H),7.28 (d, J =4.8 Hz, 1 H), 6.91 (d, J =2.6 Hz, 1 H), 4.70-3.55 (m, 5 H),2.40-2.12 (m, 2 H); MS: (ES) m/z calculated for C₁₉H₁₇ClN₈O [M+H]⁺409.2, found 409.

+++ +++ Compound 1.113: ¹H NMR (400 MHz, CD₃OD) δ8.80 (d, J =5.9 Hz, 1H), 8.38 (d, J =2.3 Hz, 1 H), 7.79-7.68 (m, 4 H), 7.59- 7.48 (m, 2 H),7.14 (dt, J =2.8, 8.6 Hz, 1 H), 6.98 (d, J =2.4 Hz, 1 H), 6.95 (dd, J =2.6, 4.4 Hz, 1 H), 6.86 (d, J =5.5 Hz, 1 H), 4.95-3.70 (br, 5 H),2.60-2.36 (m, 2 H); MS: (ES) m/z calculated for C₂₁H₁₉FN₆O [M +H]⁺391.2,found 391.

+++ +++ Compound 1.114: ¹H NMR (400 MHz, CD₃OD) δ8.37 (d, J =2.9 Hz, 1H), 7.91 (dd, J =2.6, 10.3 Hz, 1 H), 7.77 (s, 1 H), 7.71-7.68 (m, 2 H),7.61-7.55 (m, 2 H), 6.97 (d, J =2.6 Hz, 1 H), 6.92 (dd, J =2.6, 4.4 Hz,1H), 6.84 (d, J =5.9 Hz, 1 H), 4.95- 3.70 (br, 5 H), 2.60-2.36 (m, 2 H);MS: (ES) m/z calculated for C₂₁H₁₈ClFN₆O [M +H]⁺ 425.2, found 425.

+++ +++ Compound 1.115: ¹H NMR (400 MHz, CD₃OD) δ8.03 (d, J =2.2 Hz, 1H), 7.75 (s, 1 H), 7.70 (d, J =5.5 Hz, 1 H), 7.60-7.48 (m, 5 H), 6.98(d, J =2.5 Hz, 1 H), 6.91 (dd, J =2.6, 4.4 Hz, 1 H), 6.82 (d, J =5.8 Hz,1 H), 4.95-3.65 (br, 5 H), 3.93 (s, 2 H), 2.55- 2.30 (m, 2 H); MS: (ES)m/z calculated for C₂₃H₂₁N₇O [M +H]⁺412.2, found 412.

+++ ++ Compound 1.116: ¹H NMR (400 MHz, DMSO) δ8.68 (s, 1 H), 8.54 (d, J=6.9 Hz, 1 H), 8.08-8.04 (m, 2 H), 7.66 (d, J =4.4 Hz, 1 H), 7.47-7.38(m, 3 H), 6.94 (d, J = 4.4 Hz, 1 H), 6.51 (d, J =2.2 Hz, 1 H), 4.52-4.46 (m, 1 H), 3.70-3.55 (m, 4 H), 2.48 (s, 3 H), 2.26-1.90 (m, 2 H);MS: (ES) m/z calculated for C₂₂H₂₀FN₅O₂ [M +H]⁺406.2, found 406.

+++ +++ Compound 1.117: ¹H NMR (400 MHz, DMSO) δ9.38 (s, 1 H), 8.88 (d,J =7.3 Hz, 1 H), 7.90 (d, J =7.3 Hz, 2 H), 7.65 (d, J = 4.7 Hz, 1 H),7.59 (t, J =7.3 Hz, 2 H), 7.47- 7.43 (m, 2 H), 6.92 (d, J =4.7 Hz, 1 H),6.51 (d, J =2.6 Hz, 1 H), 4.52-4.48 (m, 1 H), 3.75-3.55 (m, 4 H), 2.48(s, 3 H), 2.26- 1.90 (m, 2 H); MS: (ES) m/z calculated for C₂₁H₂₁N₇O [M+H]⁺388.2, found 388.

+++ +++ Compound 1.118: ¹H NMR (400 MHz, CD₃OD) δ8.73 (s, 1 H), 7.76 (d,J =2.6 Hz, 1 H), 7.70 (d, J =5.5 Hz, 1 H), 7.55 (d, J = 4.0 Hz, 1 H),7.50-7.32 (m, 4 H), 6.92 (dd, J =2.5, 4.4 Hz, 1 H), 6.83 (d, J =5.9 Hz,1 H), 4.95-4.80 (m, 1 H), 4.70-3.70 (br, 5 H), 2.60-2.30 (m, 2 H), 2.22(s, 3 H); MS: (ES) m/z calculated for C₂₁H₂₁N₇O [M +H]⁺ 388.2, found388.

+++ ++ Compound 1.119: ¹H NMR (400 MHz, DMSO) δ9.41 (s, 1 H), 8.92 (d, J=7.0 Hz, 1 H), 7.94 (d, J =7.0 Hz, 2 H), 7.66 (d, J = 7.0 Hz, 2 H),7.50-7.48 (m, 2 H), 6.94 (d, J =4.8 Hz, 1 H), 6.82 (d, J =4.4 Hz, 1 H),6.61 (dd, J =2.6, 4.4 Hz, 1 H), 4.60-4.58 (m, 1 H), 4.10-3.70 (m, 4H),2.26-2.10 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₈ClN₇O [M+H]⁺408.2, found 408.

+++ +++ Compound 1.120: ¹H NMR (400 MHz, DMSO) δ9.38 (s, 1H) 8.15 (d, J=7.3 Hz, 1 H), 7.74 (t, J =7.7 Hz, 2 H), 7.65 (t, J = 7.7 Hz, 2 H),7.54-7.48 (m, 2 H), 6.95 (d, J =4.8 Hz, 1 H), 6.83 (d, J =4.0 Hz, 1 H),6.62 (dd, J =2.6, 4.0 Hz, 1 H), 4.62-4.58 (m, 1 H), 4.10-3.80 (m, 4 H),2.28-2.10 (m, 2 H); MS: (ES) m/z calculated for C₂₀H₁₈N₆O₂ [M +H]⁺375.2,found 375.

+++ +++ Compound 1.121: ¹H NMR (400 MHz, DMSO) δ9.40 (s, 1 H), 8.15 (d,J =7.0 Hz, 2 H), 7.87 (s, 1 H), 7.76-7.68 (m, 2 H), 7.65 (t, J =8.0 Hz,1 H), 7.50 (s, 1 H), 7.26 (d, J =4.4 Hz, 1 H), 4.62-4.58 (m, 1 H), 4.50-3.80 (br, 4 H), 2.38-2.10 (m, 2 H); MS: (ES) m/z calculated forC₁₉H₁₇N₇O₂ [M +H]⁺ 376.2, found 376.

+++ +++ Compound 1.122: ¹H NMR (400 MHz, DMSO) δ9.20 (s, 1 H), 8.71(s, 1H), 8.63 (d, J =7.0 Hz, 1 H), 8.07-8.03 (m, 2 H), 7.75 (d, J =4.4 Hz, 1H), 7.38 (t, J =9.0 Hz, 2 H), 7.29 (d, J =4.4 Hz, 1 H), 4.70-3.50 (br, 5H), 2.38-2.10 (m, 2 H); MS: (ES) m/z calculated for C₁₉H₁₆FN₇O₂ [M+H]⁺394.2, found 394.

+++ +++ Compound 1.123: ¹H NMR (400 MHz, CD₃OD) δ8.62 (d, J =5.9 Hz, 1H), 7.88 (d, J =2.5 Hz, 1 H), 7.75 (s, 1 H), 7.70 (d, J = 5.9 Hz, 1 H),7.54 (d, J =3.6 Hz, 1 H), 7.40 7.25 (m, 4 H), 6.94 (d, J =2.2 Hz, 1 H),6.91 (dd, J =2.6, 4.4 Hz, 1 H), 6.82 (d, J = 5.5 Hz, 1 H), 4.95-3.65(br, 5 H), 2.58-2.30 (m, 2 H), 2.20 (s, 3 H); MS: (ES) m/z calculatedfor C₂₂H₂₂N₆O [M +H]⁺387.2, found 387.

+++ +++ Compound 1.124: ¹H NMR (400 MHz, CD₃OD) δ8.87 (d, J =6.7 Hz, 1H), 8.26 (s, 1 H), 8.07-8.01 (m, 2 H), 7.79 (dd, J =1.2, 2.7 Hz, 1 H),7.74 (d, J =5.5 Hz, 1 H), 7.59 (d, J =4.3 Hz, 1 H), 7.51-7.46 (m, 3 H),6.95 (dd, J =2.3, 4.4 Hz, 1 H), 6.87 (d, J = 5.5 Hz, 1 H), 4.95-3.65(br, 5 H), 2.60-2.38 (m, 2 H); MS: (ES) m/z calculated for C₂₁H₁₉N₅OS [M+H]⁺390.2, found 390.

+++ +++ Compound 1.125: ¹H NMR (400 MHz, CD₃OD) δ8.76 (d, J =6.6 Hz, 1H), 8.49 (s, 1 H), 8.10-8.06 (m, 2 H), 7.79 (dd, J =1.2, 2.4 Hz, 1 H),7.74 (d, J =5.5 Hz, 1 H), 7.59 7.50 (m, 4 H), 6.95 (dd, J =2.7, 4.2 Hz,1 H), 6.87 (d, J =5.4 Hz, 1 H), 4.95-3.65 (br, 5 H), 2.60-2.30 (m, 2 H);MS: (ES) m/z calculated for C₂₁H₁₉N₅O₂ [M +H]⁺374.2, found 374.

+++ +++ Compound 1.126: ¹H NMR (400 MHz, DMSO) δ11.55 (s, 1 H), 9.35 (s,1 H), 9.11 (d, J =7.0 Hz, 2 H), 7.85-7.75 (m, 4 H), 7.55-7.35 (m, 4 H),6.90-6.80 (m, 2 H), 4.80-3.60 (br, 5 H), 2.38-2.10 (m, 2 H); MS: (ES)m/z calculated for C₂₀H₁₉N₇O [M +H]⁺374.2, found 374.

+++ ++ Compound 1.127: ¹H NMR (400 MHz, DMSO) δ9.40 (s, 1 H), 9.20 (s, 1H), 9.00 (d, J =7.0 H, 1 H), 7.90 (d, J =8.0 Hz, 2 H), 7.75 (d, J =4.7Hz, 1 H), 7.59 (t, J =7.3 Hz, 2 H), 7.46 (t, J =7.3 Hz, 1 H), 7.29 (d, J= 4.4 Hz, 1 H), 4.70-3.50 (br, 5 H), 2.38-2.10 (m, 2 H); MS: (ES) m/zcalculated for C₁₈H₁₇N₉O [M +H]⁺376.2, found 376.

+++ +++ Compound 1.128: ¹H NMR (400 MHz, CD₃OD) δ8.26 (s, 1 H), 7.87(dd, J =4.8, 9.2 Hz, 2 H), 7.77 (d, J =2.6 Hz, 1 H), 7.71 (d, J =5.5 Hz,1 H), 7.56 (d, J =4.4 Hz, 1 H), 7.25 (t, J =9.2 Hz, 2 H), 6.95 (d, J=2.5 Hz, 1 H), 6.92 (dd, J =2.6, 4.4 Hz, 1 H), 6.84 (d, J =5.5 Hz, 1 H),4.95-3.65 (br, 5 H), 2.58-2.30 (m, 2 H); MS: (ES) m/z calculated forC₂₁H₁₉FN₆O [M +H]⁺ 391.2, found 391.

+++ +++ Compound 1.129: ¹H NMR (400 MHz, CD₃OD) δ8.76 (d, J =6.2 Hz, 1H), 8.31 (s, 1 H), 7.86 (d, J =8.8 Hz, 2 H), 7.77 (d, J = 2.5 Hz, 1 H),7.72 (d, J =5.5 Hz, 1 H), 7.57 (d, J =5.5 Hz, 1 H), 7.50 (d, J =8.8 Hz,2 H), 6.96 (d, J =2.5, 1 H), 6.93 (dd, J =2.6, 7.0 Hz, 1 H), 6.84 (d, J=5.9 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.70-3.70 (br, 4 H), 2.60-2.30 (m, 2H); MS: (ES) m/z calculated for C₂₁H₁₉ClN₆O [M +H]⁺407.2, found 407.

Biological Example 1

To demonstrate that the compounds described above are useful modulatorsfor chemokine binding to CXCR7, the compounds were screened in vitro todetermine their ability to displace SDF-1 from the CXCR7 receptor atmultiple concentrations. The compounds were combined with cellsexpressing the CXCR7 receptor (e.g., MCF cells or cells transfected toexpress CXCR7) in the presence of the ¹²⁵I-labeled SDF-1 chemokine asdetailed in Determination of IC₅₀ values, Reagents and Cells (seebelow). The ability of the compounds to displace the labeled chemokinefrom the CXCR7 receptor sites at multiple concentrations was thendetermined with the screening process.

Compounds that were deemed effective modulators were able to displace atleast 50% of the SDF-1 from the CXCR7 receptor at concentrations at orbelow 15 micromolar (μM) but >2500 nM (+); and more preferably atconcentrations from >500 nM to ≤2500 nM (++). At present, especiallypreferred compounds can displace at least 50% of the SDF-1 from theCXCR7 receptor at concentrations at or below 500 nM (+++). Exemplarycompounds that met these criteria are reproduced in Table 1 and theExamples above. In Table 1, Avg Bind IC50 refers to the Buffer BindingAnalysis described below, while Avg Ser IC50 refers to the Serum BindingAnalysis described below. All compounds were prepared as described inthe Examples above, or by related methods substituting readily availablestarting materials.

1. Determination of IC₅₀ Values.

Reagents and Cells. ¹²⁵I-labeled SDF-1 was purchased from Perkin-ElmerLife Sciences, Inc. (Boston, MA). The MCF-7 (adenocarcinoma; mammarygland) cell line was obtained from the American Type Culture Collection(ATCC, Manassas, VA) or and was cultured in DMEM (Mediatech, Herndon,VA) supplemented with 10% fetal bovine serum (FBS) (HyClone Logan, UT)and bovine insulin (0.01 mg/mL) (Sigma, St. Louis, MO) at 37° C. in ahumidified incubator at a 5% CO₂/air mixture. CXCR7 transfectedMDA-MB-435S were produced as described below. MDA-MB-435S human breastcancer line, was purchased from ATCC, and cultured in DMEM/10% FBSmedium. The complete coding sequence of the gene encoding CXCR7 (a.k.a.CCXCKR2, hRDC1), was isolated from MCF-7 cells using μMACs mRNAisolation kit (Miltenyi Biotec, Auburn, CA). DNA contamination wasremoved by DNase digestion via RNeasy columns (Qiagen, Inc., Valencia,CA) and cDNA was generated using GeneAmp RNA PCR Core Kit (AppliedBiosystems, Foster City, CA). PCR of cDNA samples was performed usingTaq PCR Master Mix kit (Qiagen, Inc.) and hRDC1 primers harboring 5′ and3′ Not I sites (hRDC1F 5′

hRDC1 primers harboring 5′ and 3′ Not I sites (hRDC1F 5′GAATGCGGCCGCTATGGATCTGCATCTCTTCGACT-3′, hRDC1R 5′-GAATGCGGCCGCTCATTTGGTGCTCTGCTCCAAG-3′) Not I digested PCRproduct was ligated into Not I digested pcDNA3.1(+)(Invitrogen,Carlsbad, CA) and screened for orientation and sequence confirmed.Plasmid DNA was then isolated from overnight bacterial cultures byMaxiprep (Qiagen, Inc.). Plasmid DNA (10 μg) was added to MDA-MB-435scells and cells were electroporated (0.22 kV, 960 uF) via Gene Pulser(Biorad laboratories, Hercules, CA). 48 hr post-electroporation, cellswere transferred to selection medium (600 ug/ml G418).

Buffer Binding Analysis. Target compounds can be tested to determinetheir ability to bind with CXCR7 sites on MCF-7 and/or MDA-MB-435S CXCR7transfected cells. Efficiency-maximized radioligand binding usingfiltration protocols as described in Dairaghi D J, et al., HHV8-encodedvMIP-I selectively engages chemokine receptor CCR5. Agonist andantagonist profiles of viral chemokines, J. Biol. Chem. 1999 Jul. 30;274(31): 21569-74 and Gosling J, et al., Cutting edge: identification ofa novel chemokine receptor that binds dendritic cell-and T cell-activechemokines including ELC, SLC, and TECK., J. Immunol. 2000 Mar. 15;164(6):2851-6 was used.

In these assays, MCF-7 and/or MDA-MB-435S cells are interrogated withthe target compounds and the ability of these compounds to displace ¹²⁵Iradiolabeled SDF-1 assessed using the protocol described in Dairaghi andGosling. The target compounds are added to the plate to the indicatedconcentration and were then incubated with cells followed by theaddition of radiolabeled chemokine (¹²⁵I SDF-1) for 3 hr at 4° C. in thefollowing binding medium (25 mM HEPES, 140 mM NaCl, 1 mM CaCl₂), 5 mMMgCl₂ and 0.2% bovine serum albumin, adjusted to pH 7.1). All assays arethen incubated for 3 hrs at 4° C. with gentle agitation. Followingincubation in all binding assays, reactions are aspirated ontoPEI-treated GF/B glass filters (Packard) using a cell harvester(Packard) and washed twice (25 mM HEPES, 500 mM NaCl, 1 mM CaCl₂, 5 mMMgCl₂, adjusted to pH 7.1). Scintillant (MicroScint 10, Packard) isadded to the wells, and the filters counted in a Packard Topcountscintillation counter. Data are analyzed and plotted using GraphPadPrism (GraphPad Software).

Serum Binding Analysis. In order to more properly assess the bindingefficacy of the compounds, radioligand binding assays were carried outin the presence of 100% human serum to more accurately reflect the invivo environment. While observed IC50 values are typically lower thanthose reported for buffer binding assays, the relevance of the assay forranking of compound efficacy is enhanced. Target compounds were testedto determine their ability to bind with CXCR7 sites on MCF-7 and/orMDA-MB-435S CXCR7 transfected cells. Efficiency-maximized radioligandbinding using filtration protocols as described in Dairaghi D J, et al.,HHV8-encoded vMIP-I selectively engages chemokine receptor CCR5. Agonistand antagonist profiles of viral chemokines, J. Biol. Chem. 1999 Jul.30; 274(31): 21569-74 and Gosling J, et al., Cutting edge:identification of a novel chemokine receptor that binds dendritic cell-and T cell-active chemokines including ELC, SLC, and TECK., J. Immunol.2000 Mar. 15; 164(6):2851-6 was used.

In these assays, MCF-7 and/or MDA-MB-435S cells were interrogated withthe target compounds and the ability of these compounds to displace 125I radiolabeled SDF-1 was assessed using the protocol described inDairaghi and Gosling. The target compounds were added to the plate tothe indicated concentration followed by addition of cells andradiolabeled chemokine (125I SDF-1), both in the following medium (humanAB serum with 10 mM HEPES added to stabilize at pH 7.4). All assays werethen incubated for 3 hrs at 4° C. with gentle agitation. Followingincubation in all binding assays, reactions were aspirated ontoPEI-treated GF/B glass filters (Packard) using a cell harvester(Packard) and washed twice (25 mM HEPES, 500 mM NaCl, 1 mM CaCl₂), 5 mMMgCl2, adjusted to pH 7.1). Scintillant (MicroScint 10, Packard) wasadded to the wells, and the filters were counted in a Packard Topcountscintillation counter. Data were analyzed and plotted using GraphPadPrism (GraphPad Software).

Transendothelial migration assay: The compounds of the invention may befurther assessed by their ability to inhibit migration of cells in atransendothelial migration assay. In this assay, the ability of a cellto migrate through a layer of endothelial cells towards a chemokinesource is analyzed. In one example of this assay 100,000 human umbillicvein endothelial cells (HUVECs, available from Lonza) are plated intothe upper chamber of a transwell culture dish with a 5 uM filter poresize (Corning Costar). Medium is added and plates placed in an incubatorovernight with 5% CO2 at 37° C. After HUVECs have adhered to the filterovernight to form a monolayer, medium containing chemokine (eg SDF-1,final concentration 10 nM) is added to the lower chamber. Then 500,000NC-37 cells (available from ATCC) are added to the upper chamber in thepresence or absence of the test compound, and plates are returned to theincubator for 3 hours to overnight. Various concentrations of compoundmay be added to different wheels to create a dose response. At the endof this incubation the upper chamber is removed and the cells in thelower chamber are quantified. The cells can be quantified for instance,by labeling with a fluorescent dye such as Cyquant® (Invitrogen, CA) andthen quantifying fluorescence on an appropriate plate reader. Data canbe analyzed and plotted using GraphPad Prism (GraphPad Software). Theefficacy of the compound is measured as its ability to inhibit themigration of these cells to the lower chamber.

In Vivo Efficacy

a) Rabbit Model of Destructive Joint Inflammation

A rabbit LPS study can be conducted essentially as described in Podolin,et al. ibid., Female New Zealand rabbits (approximately 2 kilograms) aretreated intra-articularly in both knees with LPS (10 ng). The compoundof interest (e.g. formulated in 1% methocel) or vehicle (1% methocel)are dosed orally at a 5 ml/kg dose volume at two times (2 hours beforethe intra-articular LPS injection and 4 hours after the intra-articularLPS injection). Sixteen hours after the LPS injection, knees are lavagedand cells counts performed. Beneficial effects of treatment aredetermined by reduction in the number of inflammatory cells recruited tothe inflamed synovial fluid of the knee joints. Treatment with thecompound of interest results in a significant reduction in recruitedinflammatory cells.

b) Evaluation of a Compound of Interest in a Rat Model of CollagenInduced Arthritis

A 17 day developing type II collagen arthritis study can be conducted toevaluate the effects of a compound of interest on arthritis inducedclinical ankle swelling. Rat collagen arthritis is an experimental modelof polyarthritis that has been widely used for preclinical testing ofnumerous anti-arthritic agents (see Trentham, et al., J. Exp. Med.146(3):857-868 (1977), Bendele, et al., Toxicologic Pathol. 27:134-142(1999), Bendele, et al., Arthritis Rheum. 42:498-506 (1999)). Thehallmarks of this model are reliable onset and progression of robust,easily measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation.

Female Lewis rats (approximately 0.2 kilograms) are anesthetized withisoflurane and injected with Freund's Incomplete Adjuvant containing 2mg/mL bovine type II collagen at the base of the tail and two sites onthe back on days 0 and 6 of this 17 day study. A compound of interest isdosed daily in a sub-cutaneous manner from day 0 till day 17 at aefficacious dose. Caliper measurements of the ankle joint diameter aretaken, and reduced joint swelling is taken as a measure of efficacy.

(c) Evaluation of a Compound of Interest in a Mouse Model of WoundHealing

In the wound healing studies, ICR derived male mice (24±2 g) are used.During the testing period, animals are singly housed in individualcages. Under hexobarbital (90 mg/kg, IP) anesthesia, the shoulder andback region of each animal is shaved. A sharp punch (ID 12 mm) isapplied to remove the skin including panniculus carnosus and adherenttissues. A test compound or vehicle are each administered topicallyimmediately following cutaneous injury once daily for 10 consecutivedays. A positive control, for instance an A2 adenosine receptor agonist(CGS-21680; 10 μg/mouse), may also administered topically daily over thecourse of the experiment. The wound area, traced onto clear plasticsheets, is measured by use of an Image Analyzer (Life Science ResourcesVista, Version 3.0) on days 1, 3, 5, 7, 9 and 11. The percent closure ofthe wound (%) is calculated, and wound half-closure time (CT50) isdetermined and analyzed by linear regression using Graph-Pad Prism(Graph Pad Software). Unpaired Student's t test may be applied forcomparison between the treated and vehicle groups at each measurementtime point. Differences are considered of statistical significance atP<0.05 level.

(d) Evaluation of a Compound of Interest in a Mouse Model of LungCarcinoma

Many tumor models in animals are known in the art, and may be employedto evaluate a compound of instance. For instance, in a lung carcinomaxenograft study, A549 tumor fragments (30-40 mg) are implanted into thesub cutaneous space in nude mice. Tumors are permitted to grow untilapproximately 150 mg in size (between 100 and 200 mg) at which pointmice are enrolled in the study and treatment begins. Mice are treatedwith a compound of interest or the vehicle control. Melphalan may beincluded as a positive control (9 mpk/dose, ip administration, Q4D×3).Tumors are measured twice weekly with a caliper in two dimensions andconverted to tumor mass using the formula for a prolate ellipsoid(a×b²/2), where a is the longer dimension and b is the shorterdimension, and assuming unit density (1 mm³=1 mg). Body weights may alsobe measured twice weekly to assess any adverse effects of compounddosing. Antitumor activity is assessed by the delay in tumor growth ofthe treated group in comparison to the vehicle-treated control group.

(e) Rodent Adoptive Transfer Model of Experimental AutoimmuneEncephalomyelitis

Rodent EAE is an experimental model of multiple sclerosis (MS) that hasbeen widely used for preclinical testing of numerous agents for thetreatment of relapsing remitting and progressive MS. The hallmarks ofthis model are reliable onset and progression of robust, easilymeasurable paralysis of tail and limbs, neuronal inflammation, markeddemyelination in response to neural antigens.

Mice are injected with the appropriate neuronal antigen (e.g. mylinbasic protein, myelin oligodendrocyte glycoprotein, proteolipid protein)in complete Freunds adjuvant at day 0. Immune cells are harvested postCFA/antigen injections and stimulated ex vivo with cytokines andneuronal antigen, to generate a T-cell line with specificity for theneuronal antigen. These cells are then transferred into recipient mice.A compound of interest is dosed daily in a sub-cutaneous,intra-peritoneally, or oral manner from day 0 till end of study at anefficacious dose. Daily observations of degree of paralysis are taken asmeasures of efficacy.

(f) Evaluation of a Compound of Interest in a Mouse Model ofGlioblastoma

Many tumor models in animals are known in the art, and may be employedto evaluate a compound of instance. For instance, in a murineglioblastoma model, 1×10⁶ U251MG cells are implanted by stereotacticinjection into the into the brains of nude mice. After 20 days tumorsare irradiated with between 1-15 Gy of radiation. Following irradiationmice are treated (eg via subcutaneous, intraperitoneal, oral, parenteralor other route) with compound or vehicle control and tumors are allowedto progress. Tumor growth and/or mortality are monitored for theremainder of the study. Tumors are measured twice weekly with a caliperin two dimensions and converted to tumor mass using the formula for aprolate ellipsoid (a×b²/2), where a is the longer dimension and b is theshorter dimension, and assuming unit density (1 mm³=1 mg). Body weightsmay also be measured twice weekly to assess any adverse effects ofcompound dosing. Antitumor activity is assessed by the delay in tumorgrowth of the treated group in comparison to the vehicle-treated controlgroup.

(g) Evaluation of a Compound of Interest in a Rat Model of Glioblastoma

Many tumor models in animals are known in the art, and may be employedto evaluate a compound of instance. For instance, in a rat C6 model ofglioblastoma, 1×10⁶ C6 cells were implanted by stereotactic injectioninto the into the brains of Sprague-Dawley rats. After 7 days tumorswere irradiated with between 5-20 Gy of radiation. Following irradiationrats were treated (eg via subcutaneous, intraperitoneal, oral,parenteral or other route) with compound or vehicle control and tumorsare allowed to progress. Animals were followed until death or lossof >20% weight, or removed for tumor induced neurodeficits eg seizuresand immobility in according with appropriate regulations and standards.Compound activity was determined by Kaplan Meier analysis of survivaland Compound 1.090 in Table 1 had profound antitumor activity asassessed by the delay in tumor growth of the treated group in comparisonto the vehicle treated control group.

(h) Evaluation of a Compound of Interest in a Mouse Model ofHypertension

Many models of pulmonary dysfunction and hypertension in animals areknown in the art, and may be employed to evaluate a compound ofinstance. For instance, in a chronic hypoxia-induced pulmonaryhypertension model, newborn mice (FVB/NJ) are randomly exposed tonormobaric normoxia (Room Air (RA)) or hypoxia (HA) (FiO2=0.12) for 2weeks. After 1 week of RA or HA, the mice are treated with the compoundof interest eg daily subcutaneous injections of a vehicle or compoundfrom postnatal day 7 to day 14. The degree of pulmonary hypertension canbe determined by measuring right ventricular systolic pressure (RVSP).Briefly, a thoracotomy is performed and a 25 gauge needle connected apressure transducer (Gould Instruments, OH) is inserted into the rightventricle and RSVP recorded. Immediately after RVSP measurements themice are sacrificed, heart removed and dissected. Right ventricularhypertrophy (RVH) is assessed by the ratio of the weight of rightventricle to the left ventricle+septum (RV/LV+S). Improvements inmeasurements of RSVP and RVH indicate that the candidate compound hastherapeutic capacity.

Validation

Compounds that are initially identified as being of interest by any ofthe foregoing screening methods can be further tested to validate theapparent activity in vivo. Preferably such studies are conducted withsuitable animal models. The basic format of such methods involvesadministering a lead compound identified during an initial screen to ananimal that serves as a disease model for humans and then determining ifthe disease (e.g., cancer, myocardial infarction, wound healing,inflammatory diseases or other diseases associated with CXCR7) is infact modulated and/or the disease or condition is ameliorated. Theanimal models utilized in validation studies generally are mammals ofany kind. Specific examples of suitable animals include, but are notlimited to, primates, mice, rats and zebrafish.

SEQUENCE LISTING CXCR7 coding sequence SEQ ID NO: 1ATGGATCTGCATCTCTTCGACTACTCAGAGCCAGGGAACTTCTCGGACATCAGCTGGCCATGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCGGCAGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTATCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGCTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTCTCAGAGACGGAGTACTCTGCCTTGGAGCAGAGCACCAAATGA CXCR7 amino acid sequenceSEQ ID NO: 2 MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFSINLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDTYYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVSE TEYSALEQSTKCXCR7.2 coding sequence SEQ ID NO: 3ATGGATCTGCACCTCTTCGACTACGCCGAGCCAGGCAACTTCTCGGACATCAGCTGGCCATGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCAGCGGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTATCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGCTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTGTCGGAGACGGAGTACTCCGCCTTGGAGCAAAACGCCAAGTGA CXCR7.2 amino acid sequenceSEQ ID NO: 4 MDLHLFDYAEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFSINLFSGIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDTYYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASR VSETEYSALEQNAKCXCR7.3 coding sequence SEQ ID NO: 5ATGGATCTGCATCTCTTCGACTACTCAGAGCCAGGGAACTTCTCGGACATCAGCTGGCCATGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCGGCAGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTGTCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGTTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTCTCAGAGACGGAGTACTCTGCCTTGGAGCAGAGCACCAAATGA CXCR7.3 amino acid sequenceSEQ ID NO: 6 MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFSINLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDTYYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIVAVFYFLLARAISASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVS ETEYSALEQSTKCXCR7.4 coding sequence SEQ ID NO: 7ATGGATCTGCATCTCTTCGACTACTCAGAGCCAGGGAACTTCTCGGACATCAGCTGGCCATGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCGGCAGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTATCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGCTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTCTCAGAGACGGAGTACTCTGCCTTGGAGCAGAGCACCAAATGA CXCR7.4 amino acid sequenceSEQ ID NO: 8 MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFSINLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDTYYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVSE TEYSALEQSTKCXCR7.5 coding sequence SEQ ID NO: 9ATGGATCTGCATCTCTTCGACTACTCAGAGCCAGGGAACTTCTCGGACATCAGCTGGCCGTGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCAGCAGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTATCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGTTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTCTCAGAGACGGAGTACTCCGCCTTGGAGCAGAGCACCAAATGA CXCR7.5 amino acids equenceSEQ ID NO: 10MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFSINLFSSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDTYYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVSE TEYSALEQSTK

One of ordinary skill in the art will recognize from the provideddescription, FIGURES, and examples, that modifications and changes canbe made to the various embodiments of the invention without departingfrom the scope of the invention defined by the following claims andtheir equivalents.

All patents, patent applications, publications and presentationsreferred to herein are incorporated by reference in their entirety. Anyconflict between any reference cited herein and the teaching of thisspecification is to be resolved in favor of the latter. Similarly, anyconflict between an art-recognized definition of a word or phrase and adefinition of the word or phrase as provided in this specification is tobe resolved in favor of the latter.

What is claimed is:
 1. A compound having formula I

or a pharmaceutically acceptable salt, hydrate, N-oxide, isotopicallyenriched or enantiomerically enriched version or a rotamer thereof,wherein each of ring vertices X^(a), X^(b) and X^(c) is independentlyselected from the group consisting of N, NH, N(R²), O, CH and C(R²); thesubscript n is 0, 1 or 2; Z is selected from the group consisting of

R¹ is a member selected from the group consisting of H and C₁₋₈ alkyl,wherein the alkyl portion is optionally substituted with halogen,—NR^(a)R^(b), —OR^(a), —CO₂R^(a) and —CONR^(a)R^(b); each R² isindependently selected from the group consisting of H and C₁₋₄ alkyl; R³is a member selected from the group consisting of H, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ hydroxyalkyl, —CO₂R^(a), —X—CO₂R^(a), —CONR^(a)R^(b) and—X—CONR^(a)R^(b); each R⁴, when present, is a member independentlyselected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈hydroxyalkyl, —OR^(a), —CO₂R^(a), —X—CO₂R^(a), —NR^(a)R^(b),—CONR^(a)R^(b) and —X—CONR^(a)R^(b); R⁵ is selected from the groupconsisting of substituted aryl, heteroaryl, cycloalkyl, andheterocycloalkyl optionally further substituted with 1-3 R^(a); eachR^(a) and R^(b) is independently selected from the group consisting ofhydrogen, hydroxyl, halogen, cyano, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylalkyl, amino, C₁₋₈alkylamino, di C₁₋₈ alkylamino, carboxamide, carboxy C₁₋₄ alkyl ester,carboxylic acid, and —SO₂— C₁₋₈ alkyl; each X is a C₁₋₄ alkylene linkinggroup or a linking group having the formula —(CH₂)_(m)O(CH₂)_(p)—,wherein the subscripts m and p are integer of from 0 to 5, and m+p isfrom 0 to 6, wherein any of the methylene portions of X are optionallysubstituted with one or two methyl groups.
 2. The compound of claim 1,wherein Z is monocyclic heteroaryl selected from the group consisting ofimidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,thiazole, oxazole, oxadiazole, pyrimidine, pyrazine, and pyridazine,each of which is optionally substituted with 1 R⁵ substituents.
 3. Thecompound of claim 1, wherein R¹ is H.
 4. The compound of claim 1,wherein R³ is selected from the group consisting of H, CH₂OH andC(O)NH₂.
 5. The compound of claim 1, having the structure:


6. The compound of claim 5, wherein the bicyclic portion having X^(a),X^(b) and X^(c) as ring vertices is selected from the group consistingof:


7. The compound of claim 5, wherein Z has the formula:

wherein each Q is independently selected from the group consisting of N,and CH.
 8. The compound of claim 1, having the formula:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim8, wherein R^(a) is selected from the group consisting of selected fromthe group consisting of hydrogen, halogen, cyano, C₁₋₈ alkyl and —SO₂—C₁₋₈ alkyl.
 10. The compound of claim 8, wherein R² is selected from thegroup consisting of H and C₁₋₄ alkyl.
 11. The compound of claim 8,wherein R^(a) is selected from the group consisting of hydrogen,halogen, cyano, C₁₋₈ alkyl and —SO₂— C₁₋₈ alkyl; and R² is selected fromthe group consisting of H and C₁₋₄ alkyl.
 12. A compound of claim 1,having the formula:

or a pharmaceutically acceptable salt thereof.
 13. A compound of claim1, having the formula:

or a pharmaceutically acceptable salt thereof.
 14. A compound of claim1, having the formula:

or a pharmaceutically acceptable salt thereof.